JP2003531201A - 2-Fluorobenzenesulfonyl compounds for treating inflammation - Google Patents

Abstract

(57) [Summary] Formula (I) Wherein A, R1, R2, and R3 are as described in the description. A method for treating a cyclooxygenase-2-mediated disease, comprising administering an amount. And a novel 2-fluorobenzenesulfonyl compound included in the formula (I).

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention is in the field of anti-inflammatory pharmaceutical formulations, and is generally cyclooxygenase-
It relates to compounds, compositions and methods for treating 2 mediated diseases such as inflammation and inflammation-related diseases. The present invention particularly relates to 2-fluorobenzenesulfonyl compounds, compositions and methods for treating cyclooxygenase-2 mediated disorders.

BACKGROUND prostaglandin of the invention, plays a major role in the inflammatory process, the production of prostaglandins, in particular, inhibition of PGG _2, PGH ₂ and production of PGE _2, the common target of finding an anti-inflammatory agent Is. Generic non-steroidal anti-inflammatory drugs (“N”) active in reducing prostaglandin-induced pain and swelling associated with inflammatory processes.
SAIDs "), however, are also active in adversely affecting other prostaglandin-regulatory processes that are not associated with inflammatory processes. Severe side effects, including associated ulcers, can occur, which limits their therapeutic potential.
Alternatives to AIDs include the use of corticosteroids, which have even more drastic side effects, especially when involved in long-term treatment.

Conventional NSAIDs have been found to prevent prostaglandin production by inhibiting enzymes in the human arachidonic acid / prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of inducible enzymes associated with inflammation has revealed clear targets for inhibition that reduce inflammation more efficiently and with less drastic side effects.

Recently, significant research has been conducted on some roles of cyclooxygenase-2. Lung cancer (T. Hida et al., Anticancer Res)
． , 18, 775-82 (1998)), Barrett's esophagus (K. Wilson,
Cancer Res. , 58, 2929-34 (1998)) and skin cancer (
S. Buckman et al. , Carcinogenesis, 19, 7
23-29 (1998)), including benign and malignant tumors (K. Subbara).
maiah et al. , Proc. Soc. Exp. Biol. Med. ，
216, 201 (1997), COX-2 was found to have a regulatory function. For asthma, it is expressed in the respiratory tract (P. Bar.
nes et al. , Lung Biol. Health Dis. , 114
, 111-27 (1998)). COX-2 is also, among other things, preterm labor, angiogenesis (M. Tsuji et al., Cell, 93, 705-16 (19).
98)), vascular rejection (M. Bustos, J. Clin. Invest., 10).
0,1150-58 (1997)), HIV-induced cell extinction (G. Bagetta).
et al. , Biochem. Biophys. Res. Commun. ，
244, 819-24 (1998)), neurodegeneration.
(T. Sandhya et al., Brain Res., 78).
8, 223-31 (1998)), inflammatory bowel disease, colitis (I. Singer e.
t al. , Gastroenterology, 115, 297-306 (1
998)), cerebral ischemia (S. Nogawa et al., Proc. Nat.
l. Acad. Sci. , 95, 10966-71 (1998)) and hypertension (A. Nasjetti, Hypertension, 31, 194-200 (A.
1997)).

Drugs that inhibit cyclooxygenase are among others colon cancer (T. Kawam).
ori et al. , Cancer Res. , 58, 409-12 (199
8)), allergic neuritis (K. Miyamoto et al., Neuro.
Report, 9, 2331-4 (1998)), dementia, fever infection (M. Sh
Oup, J .; Trauma: Inj. INFEC. , Crit care, 45
, 215-21 (1998)), cytomegalovirus infectivity (E. Spair).
, Et al. , Circ. Res. , 83, 210-16 (1998)) and low back pain (H. Bosch, Curr. Med. Res. Opin., 14, 29).
-38 (1997)).

The following references disclose compounds with anti-inflammatory activity and show ongoing efforts to find safe and effective anti-inflammatory agents. WO96 / 19463
Selective inhibition of cyclooxygenase-2 [(2- or 3) -halo-4-
(Alkylsulfonyl, aminosulfonyl or alkylaminosulfonyl)]
Oxazoles substituted with phenyl groups are described. U. S Patent No. 5,
380,738 describes 4-fluoro-phenyl and 4-methylsulfonyl substituted oxazoles that selectively inhibit cyclooxygenase-2. U. S. Patent No. 5,719,163 describe substituted oxazoles that selectively inhibit cyclooxygenase-2. WO96 / 3661
7 describes oxazoles that selectively inhibit cyclooxygenase-2. WO96 / 19462 describes oxazoles that selectively inhibit cyclooxygenase-2. WO98 / 11080 describes 3,4-diaryl-oxazolones that selectively inhibit cyclooxygenase-2.

EP 799,823 A1 describes 1- or 2- [3-halo-4- (methylsulfonyl, aminosulfonyl or substituted aminosulfonyl) phenyl] -pyrroles which selectively inhibit cyclooxygenase-2. is doing. U. S
． Patent No. 5,935,990 describe substituted pyrroles that selectively inhibit cyclooxygenase-2.

WO 99/64415 discloses 1- (as intermediates used in the preparation of sulfonylbenzene compounds containing aryl or heteroaryl substituted phenyl moieties.
4-Bromophenyl) -2- [3-fluoro-4- (methylsulfonyl) phenyl] -5-methyl-1H-pyrrole; 5- (4-bromophenyl) -1- [3-
Fluoro-4- (methylsulfonyl) phenyl] -3- (hydrogen, cyano, nitro, trifluoromethyl or ethoxycarbonyl) -1H-pyrrole; 2-[(
4-bromophenyl) or (3-methyl-4-bromophenyl)]-1- [3
-Fluoro-4- (methylsulfonyl) phenyl] -4-trifluoromethyl-
1H-imidazole; 4- [2- (4-bromophenyl) -4-hydroxy-4
-Trifluoromethyl-1H-imidazol-1-yl] -2-fluorobenzenesulfonamide; 3- (4-bromophenyl) -4- [3-fluoro-4- (
Methylsulfonyl 9phenyl] -2- (5H) -furanone; 3- (4-Bromophenyl) -4- [3-fluoro-4- (methylsulfonyl or aminosulfonyl) phenyl] -5-methylisoxazole; 4- (4-bromophenyl)-
5- [3-fluoro-4- (methylsulfonyl or aminosulfonyl) phenyl] -2-methyl-1,3-oxazole; and 4- (3-methyl-4-bromophenyl) -5- [3-fluoro -4- (methylsulfonyl) phenyl]-
2-Methyl-1,3-oxazole is described. WO99 / 64415
The disclosed sulfonylbenzene compounds are described as useful in the treatment of cyclooxygenase-mediated diseases.

U. S. Patent No. 5,466,823, 5,504,215, 5,508,
426, 5,510,496, 5,516,907, 5,521,207 and 5,760,068 describe substituted pyrazole benzene sulfonamides that selectively inhibit cyclooxygenase-2. U. S. Patent No. 5
, 475,018 describes 1,5-diphenylpyrazoles that selectively inhibit cyclooxygenase. U. S. Patent No. 5,486,534 and 5,756,529 selectively inhibit cyclooxygenase-2 3,4
-Describes substituted pyrazoles. U. S. Patent No. 5,401,7
65 and 5,639,777 describe 1,4,5-trisubstituted pyrazoles that selectively inhibit cyclooxygenase-2. U. S. Patent No.
5,434,178 and 5,908,852 describe 1,3,5-trisubstituted pyrazoles that selectively inhibit cyclooxygenase-2.

WO 94/15934 describes thiophene and furan derivatives that selectively inhibit cyclooxygenase-2. WO94 / 26731 describes thiophene compounds that selectively inhibit cyclooxygenase. WO97 /
16435 describes 3,4-diaryl-2-hydroxy-2,5-dihydrofurans as prodrugs of compounds that are cyclooxygenase-2 inhibitors. GB 2,294,879 describes substituted furanones as cyclooxygenase-2 inhibitors.

U. S. Patent No. 5,859,257 describes substituted isoxazoles that selectively inhibit cyclooxygenase-2. EP745596
Describes substituted isoxazoles that selectively inhibit cyclooxygenase-2.

U. S. Patent No. 5,344,991, 5,420,287 and 5,66
3,180 describes substituted cyclopentenes that selectively inhibit cyclooxygenase-2.

U. S. Patent No. 5,418,254 describes substituted cyclopentadienyls that selectively inhibit cyclooxygenase-2. U. S. Patent No. 5,916,905 describe 2,3-substituted pyridines that selectively inhibit cyclooxygenase-2. U. S. Patent No
． 5,596,008 selectively inhibits cyclooxygenase-2 3,4
-Diaryl substituted pyridines are described. WO98 / 03484
Described are substituted pyridines that selectively inhibit cyclooxygenase-2.

U. S. Patent No. 5,393,790 and 5,736,579 describe substituted spiro compounds that selectively inhibit cyclooxygenase. U. S. Patent No. 5,670,510, 5672,626 and 5,672
, 627 describe spirodienes that selectively inhibit cyclooxygenase-2.

U. S. Patent No. 5,668,161 describes substituted thiazoles that selectively inhibit cyclooxygenase-2. U. S. Patent No. 5,616,601 describes 1,2-substituted imidazoles that selectively inhibit cyclooxygenase-2. WO96 / 0
3387 describes 4,5-substituted imidazoles that selectively inhibit cyclooxygenase-2. WO96 / 03388 describes 1,2-substituted imidazoles that selectively inhibit cyclooxygenase-2.
U. S. Patent No. 5,521,193 and 5,534,521 describe benzimidazoles that selectively inhibit cyclooxygenase-2.

WO94 / 13635 selectively inhibits cyclooxygenase-2 5-
The methanesulfonamide-1-indanones are described. WO94 / 2048
0 is alkanesulfonamide-which selectively inhibits cyclooxygenase-2
1-Indanones are listed.

WO96 / 09293 describes benz [g] indazolyls which selectively inhibit cyclooxygenase-2. Wo98 / 47890 describes benzopyran derivatives that selectively inhibit cyclooxygenase-2. U. S. Patent No. 5,886,016 describes benzopyranopyrazolyls that selectively inhibit cyclooxygenase-2. U. S. Patent No. 5,565,482 is cyclooxygenase-2
Heteroarylpyranopyrazolyls are described which selectively inhibit the.

U. S. Patent No. 5,739,166 describes substituted terphenyls that selectively inhibit cyclooxygenase-2. Finally, various further substituted sulfonamides are described. Pyrazolyl-sulfonylureas have been described to have potential hypoglycemic activity [H. Faid-Allah and H.M. Mokhtar, Ind. J. C
hem. 27, 245 (1998)]. JP 1,045,374 describes water-soluble tetrazolium compounds useful in assays for measuring reducing substances. D. Mukerjee et al [Acta. Pharma. Jugosl
． , 31, 151 (1981)] describes tetrazolium sulfonamides as antiviral agents. JP 5,323,522 describes the use of heterocyclic rings in black and white photographic materials. U. S. Patent No. 5,389,635 describes imidazoles substituted as angiotensin II antagonists. U. S. Patent No. 5,387,592 describes benzimidazole derivatives substituted as angiotensin II antagonists. G.
Dorofenko et al [Khim. Farm. Zh. , 16, 92
0 (1982)] describe pyridinium salts as antiviral agents. U
． S. Patent No. 5,338,749 describes diaryl substituted heterocyclyl compounds as anti-arthritic agents.

However, the compounds invented to date have not been described as being anti-inflammatory cyclooxygenase inhibitors.

DESCRIPTION OF THE INVENTION The present invention provides a cyclooxygenase-2 mediated disease, eg, inflammation, to a patient having or afflicted with such disease, one of formulas I-VII described below. Methods of treatment include administering a therapeutically effective amount of the above compounds. The methods of the invention also include prophylactic treatment of patients. The compounds of Formula I-VII include the class of 2-fluorobenzenesulfonyl compounds that are safe and effective anti-inflammatory agents. These compounds generally exhibit improved selectivity and / or potency over cyclooxygenase-1 over cyclooxygenase-2 as compared to the corresponding sulfonamides or methyl sulfones lacking orthofluoro substituents. The present invention further includes novel 2-fluorobenzenesulfonyl compounds that fall into the class of compounds of Formulas I-VII.

More specifically, the present method of treating a cyclooxygenase-2 mediated disease is of formula I:

[0022]

[Chemical 30]

Wherein ^A is a 5- or 6-membered ring substituent selected from partially saturated or unsaturated heterocyclic and carbocyclic rings; R ¹ is cyclohexyl, Pyridinyl or phenyl, wherein cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl,
Cyano, carboxyl, C _1-2 -alkoxycarbonyl, hydroxyl, C _1-2-
Hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl, C _1-2 -alkylsulfinyl, halo, R ² is alkyl (especially methyl) or amino, which may be substituted with 1, 2 or 3 groups selected from C _1-2 -alkoxy and C _1-3 -alkylthio; ³ is hydride, halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _{1 -3} - alkoxy, C _1-3 - alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 - haloalkyl, heterocyclyl, cycloalkenyl, phenyl -C _1-3 - alkyl, Heterosa Krill -C _1-3 - alkyl, C _1-3 - alkylthio -C _1-3 - alkyl, C _1-3 - hydroxyalkyl,
C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3 -alkyl, phenylthio-C _1-3 -Alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _{1- 3} -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkylamino, N-arylamino, N - aralkylamino, N- (C _1-3 - alkyl) -N- aralkylamino, N- (C _{1 -3} - alkyl) - N-arylamino, amino-C _1-3 -alkyl, C _1-3 -alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-
C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-
C _1-3 -alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-
Phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl,
C _1-3 -alkylsulfonyl, aminosulfonyl, C _1-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3
Represents one or more groups selected from -alkyl) -N-phenylaminosulfonyl, provided that (a) A is not pyrrolyl and (b) A is not oxazolyl other than oxazolonyl. ] Or a pharmaceutically acceptable salt, tautomer or prodrug thereof, wherein the therapeutically effective amount of one or more compounds is administered to the patient. .

Of the groups of compounds described above and for the compounds disclosed in the various embodiments of this invention described throughout this application, one or more of the following conditions should preferably be fulfilled.

(1) When R ¹ is 4-bromophenyl: (a) When R ² is methyl and R ³ is hydrogen, cyano, trifluoromethyl or ethoxycarbonyl, A is
Not pyrazolyl; (b) when R ³ is trifluoromethyl, A is not imidazolyl; (c) when R ³ is methyl, A is not isoxazolyl; (d) R ³ is hydrogen Sometimes A is not 2-furanonyl; provided that R ¹ is 3-methyl-4-bromophenyl and R ² is methyl,
When R ³ is trifluoromethyl, A is not imidazolyl; (2) When R ¹ is 3-methyl-4-bromophenyl, R ² is methyl and R ³ is trifluoromethyl. , A is not imidazolyl; (3) R ¹ is other than 4-bromophenyl; (4) R ¹ is other than 4-bromophenyl or 3-methyl-4-bromophenyl; and / or (5) R ¹ is other than bromophenyl.

[0026] In another embodiment, the method of treating a cyclooxygenase-2 mediated disease comprises: 5-wherein A is selected from partially saturated or unsaturated heterocyclic and carbocyclic rings. A 6-membered ring substituent; R ¹ is cyclohexyl, pyridinyl or phenyl, and said cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl,
Cyano, carboxyl, C _1-2 -alkoxycarbonyl, hydroxyl, C _1-2-
Hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl, C _1-2 -alkylsulfinyl, halo, It may be substituted with 1, 2 or 3 groups selected from C _1-2 -alkoxy and C _1-3 -alkylthio; R ² is methyl or amino; R ³ is hydride Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, (5- or 6-membered heterocyclyl) Oxy, C _1-3 -alkoxy, C _1-3 -alkylthio, C _1-3 -alkylcarbonyl, C _3-6 -cycloalkyl, phenyl, C _1-3
-Haloalkyl, 5- or 6-membered ring heterocyclyl, C _3-6 -cycloalkenyl, phenyl-C _1-3 -alkyl, (5- or 6-membered ring heterocyclyl)
-C _1-3 -alkyl, C _1-3 -alkylthio-C _1-3 -alkyl, C _1-3 -hydroxyalkyl, C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-
C _1-3 - alkylcarbonyl, phenyl -C _2-3 - alkenyl, C _1-3 - alkoxy -C _1-3 - alkyl, phenylthio -C _1-3 - alkyl, phenyloxy -C _1-3 - alkyl, C _1-3 -alkoxyphenyl-C _1-3 -alkoxy-C _1-3 -alkyl, C _1-3 -alkoxycarbonyl-C _1-3 -alkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy- C _1-3 - alkyl, C _1-3 - alkylamino, N- phenylamino, N- (phenyl -
C _1-3 -alkyl) amino, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3
-Alkyl) amino, N- (C _1-3 -alkyl) -N-phenylamino, amino-C _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl, N-phenylamino- C _1-3 -alkyl, N-phenyl-C _1-3 -alkylamino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3 -alkylamino-
C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-phenylamino-C _1-3 -alkyl, phenyloxy, phenyl-C _1-3 -alkoxy, phenylthio, phenyl-C _1-3 - alkylthio, C _1-3 - alkylsulphinyl, C _1-3 - alkyl, aminosulfonyl, C _1-3 - alkyl aminosulfonyl, N- phenylamino, phenylsulfonyl and N-(C _1-3 - alkyl) −
From a preferred group of compounds of formula I, which represents one or more groups selected from N-phenylaminosulfonyl; or a pharmaceutically acceptable salt, tautomer or prodrug thereof. Administering to the patient a therapeutically effective amount of one or more compounds selected.

Of this class of preferred compounds, A is preferably thienyl, furyl, furanone, thiazolyl, oxothiazolyl, thioxothiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, oxooxazolyl, pyrazolyl. A cyclopentenyl, cyclopentadienyl, benzindazolyl, benzopyranopyrazolyl, phenyl and pyridyl. More preferably, A is thienyl, furyl, furanone, thiazolyl, oxothiazolyl, thioxothiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, benzindazolyl, benzo. A group selected from pyranopyrazolyl, phenyl and pyridyl. Even more preferably, A is thienyl,
A group selected from furanone, isoxazolyl, pyrazolyl, cyclopentenyl and pyridinyl. Still more preferably, A is a group selected from furanone, isoxazolyl and pyrazolyl.

In another embodiment, the method of treating a cyclooxygenase-2 mediated disease provides for one or both of R ¹ and R ³ to be as follows: R ¹ is cyclohexyl, pyridinyl or phenyl, The cyclohexyl, pyridinyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino, phenylamino, nitro, methoxymethyl, methylsulfinyl, fluoro. , Chloro, bromo, methoxy and methylthio, optionally substituted with one, two or three groups; and / or R ³ is hydride, fluoro, chloro, bromo, methyl, oxo, cyano. , Mosquito Bokishiru, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethyl, methoxycarbonyl methyl, phenylthiomethyl,
Phenyloxymethyl, methoxyphenylmethoxymethyl, methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino , N-phenylamino, N- (phenylmethyl) amino, N-methyl-N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N- Phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N-methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, Chirusuruhoniru, aminosulfonyl, methylaminosulfonyl, N- phenylamino, phenylsulfonyl and N- methyl -
A group selected from N-phenylaminosulfonyl; administering to a patient a therapeutically effective amount of one or more compounds selected from the more preferred class of compounds consisting of compounds of formula I defined as: Including doing.

[0029] In another embodiment, the method of treating a cyclooxygenase-2 mediated disease is characterized in that R ¹ is cyclohexyl or phenyl, and said cyclohexyl and phenyl are halo, cyano, C _1-2 -alkyl, C It may be substituted with 1, 2 or 3 groups selected from _1-2 -haloalkyl, C _1-2 -alkoxy and C _1-2 -haloalkoxy; R ³ is hydride, C _1- A group selected from ₂ -alkyl, C _1-3 -alkoxy, C _1-3 -alkylcarbonyl, C _1-3 -haloalkyl and C _1-3 -alkoxycarbonyl; consisting of a compound of formula I Administering to the patient a therapeutically effective amount of one or more compounds selected from the even more preferred class of compounds.

In another embodiment, the method of treating a cyclooxygenase-2 mediated disease is characterized in that R ¹ is cyclohexyl or phenyl and said cyclohexyl and phenyl are methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy. R ³ is optionally substituted with 1, 2 or 3 groups selected from cyano, fluoro, bromo and methoxy; R ³ is hydride, methyl, methoxy, methylcarbonyl, trifluoromethyl, difluoromethyl, hydroxy A group selected from methyl and methoxycarbonyl; comprising administering to the patient a therapeutically effective amount of one or more compounds selected from the even more preferred group of compounds consisting of formula I.

In another embodiment, the method of treating a cyclooxygenase-2 mediated disease is represented by Formula I except that the fluoro group is located in the meta position of the phenyl ring relative to the sulfonyl group rather than the ortho position. Administering to the patient a therapeutically effective amount of one or more compounds selected from the group consisting of compounds having a structure similar to that of the compound.

Utility of Methods and Compounds The methods and compounds of the present invention are not only useful for treating inflammation in a patient, but also for the treatment of other cyclooxygenase-2-mediated disorders, eg, in the treatment of pain and headaches. It may be useful as an analgesic or antipyretic for the treatment of fever. For example, the methods and compounds of the present invention would be useful in treating arthritis, including rheumatoid arthritis, spondyloarthropathy, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, although these It is not limited to. Such methods and compounds of the present invention include asthma; bronchitis; menstrual cramps; preterm labor; tendinitis; bursitis; allergic neuritis; cytomegalovirus infectivity;
HIV-induced apoptosis, including back pain, apoptosis; liver disease, including hepatitis;
Skin-related conditions such as psoriasis, eczema, acne, UV damage, burns and dermatitis;
For example, it may be useful for treating post-operative inflammation, including ophthalmic surgery such as cataract surgery and refractive surgery.

The methods and compounds of the present invention also provide for conditions of the gastrointestinal tract, such as inflammatory bowel disease,
It may be useful in treating Crohn's disease, gastritis, irritable enteritis syndrome and ulcerative colitis.

The methods and compounds of the present invention can be used, for example, in migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, inflammation in type I diabetes; Neuromuscular junction diseases including asthenia; white sclerosis including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity; posttraumatic injury including hydrocephalus, myocardial ischemia It may be useful in treating inflammation such as swelling.

The methods and compounds also treat ocular diseases, for example, ocular diseases such as retinitis, conjunctivitis, retinal disorders, uveitis, ocular photophobia; and acute trauma to ocular tissues. Would be useful to do.

The methods and compounds are also useful in the treatment of lung inflammation, such as those associated with viral infections and pancreatic cystic fibrosis; and bone resorption, such as that associated with osteoporosis. .

The methods and compounds also treat certain central nervous system disorders such as cortical dementia, including Alzheimer's disease, neurodegeneration; and central nerve damage resulting from stroke, ischemia and trauma. Useful to do. The term "treatment" includes the suppression of some or all of dementia, including Alzheimer's disease, vascular dementia, multiple infarctions, presenile dementia, alcoholic dementia and senile dementia.

The methods and compounds of the invention are not only useful, for example, as anti-inflammatory agents for the treatment of arthritis, but have the added convenience of having significantly less harmful side effects. These methods and compounds also provide allergic rhinitis, respiratory distress syndrome,
It is also useful in the treatment of endotoxin shock syndrome and liver disease. The methods and compounds are useful in the treatment of pain, including but not limited to post-operative pain, toothache, myalgia and pain caused by cancer.

The methods and compounds described above will be useful, but not limited to, for treating and preventing inflammation-related cardiovascular disease in patients. The methods and compounds include vascular disease; coronary artery disease; aneurysm; vascular rejection; arteriosclerosis; heart transplant atherosclerosis including atherosclerosis; myocardial infarction; embolism; stroke; thrombosis including venous thrombosis. Useful in treating and preventing inflammatory diseases; including unstable angina; angina; coronary plaque inflammatory inflammation; including Chlamydia-induced inflammation; viral-induced inflammation; coronary artery bypass surgery, for example. , Including surgical procedures such as vascular transplantation; including angioplasty, revascularization; stent placement; surgical procedures such as arterial endarterectomy; or including arteries, veins and capillaries , But may be useful for other invasive procedures, but is not limited thereto.

The methods and compounds will be useful for, but not limited to, treatment of angiogenesis-related disorders in a patient. According to the present invention, the methods and compounds include
It can be used to treat patients in need of angiogenesis inhibition. The present methods and compounds include neoplasia, including metastases; ocular conditions such as corneal transplant rejection, ocular neovascularization, neoplasia following trauma or infection, retinal neoplasia, diabetic retinopathy, macular degeneration. , Post lens fibroplasia and neovascular glaucoma; ulcerative diseases, eg gastric ulcers; pathological but non-malignant conditions such as hemangiomas, including, for example, infantile hemangiomas,
It can be used to treat nasopharyngeal angiofibromas and ischemic necrosis of bone; and disorders of the female reproductive system, such as endometritis.

The methods and compounds of the present invention are useful, for example, in colorectal cancer, brain cancer, bone cancer, epithelial cell-induced neoplasia (epithelial cancer), such as basal cell carcinoma, adenocarcinoma; , Lip cancer, oral cancer, esophageal cancer, small intestine cancer and gastric cancer; colon cancer; liver cancer; bladder cancer; pancreatic cancer; ovarian cancer; cervical cancer; lung cancer; breast cancer; and skin cancer such as squamous cell and basal cancer It is useful for preventing or treating cell carcinoma; prostate cancer; renal cell carcinoma; as well as other known cancers that affect epithelial cells throughout the body. Preferably, the neoplasm is gastrointestinal tract cancer, Barrett's esophageal cancer, liver cancer, bladder cancer; pancreatic cancer, ovarian cancer, prostate cancer,
It is selected from uterine cancer, lung cancer, breast cancer and skin cancer, for example squamous cell carcinoma and basal cell carcinoma. The methods and compounds can also be used to treat fibrosis caused by radiation therapy. The methods and compounds can be used to treat patients with adenomatous polyps due to familial adenomatous polyposis (FAP). The methods and compounds can also be used to prevent polyp formation in patients at risk for FAP.

The methods and compounds of the present invention can be used in the context of additional treatments and / or compounds known to those skilled in the art in the prevention or treatment of neoplasms or alone. Alternatively, the methods and compounds described herein can be used in related therapies. By way of example, the compounds can be administered in the context of other anti-tumor or anti-growth agents or other agents or nutrients or alone.

The methods and compounds may also be used in combination with other anti-inflammatory agents, eg, steroids, NSAIDs, iNOS inhibitors, p, in co-treatment.
38 inhibitor, MMP inhibitor, TNF inhibitor, 5-lipoxygenase inhibitor, LT
It can be used in combination with B ₄ receptor antagonists and LTA ₄ hydrolase inhibitors.

The present methods and compounds also include, among other things, opioids; and narcotic analgesics, mu receptor antagonists, kappa receptor antagonists, non-narcotic (ie, non-addictive) analgesics, monoamine absorption inhibitors, adenosine modulators. Agents, cannabinoid derivatives, substance P antagonists, neurokinin-1
It can also be used in combination therapy with other analgesics, including receptor antagonists and sodium channel blockers. Morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine, meptazinol, hydrocodone, oxycodone, methadone, tramadol [
(+) Enantiomer], DuP747, dinorphin A, enadrine, RP-
60180, HN-11608, E-2078, ICI-204448, acetominophen (paracetamol), propoxyphene, nalbuphine, E-401.
8, filenadol, milfentanil, amitriptyline, DuP631, tramadol [(-) enantiomer], GP-531, acadesin, AKI-1
, AKI-2, GP-1683, GP-3269, 4030W92, tramadol racemate, dinorphine A, E-2078, AXC3742, SNX-11.
1, ADL2-1294, ICI-204448, CT-3, CP-99,99
4 and CP-99,994 in combination with a compound selected from the above may be more preferable.

The present methods and compounds are effective in combination with one or more antihistamines, decongestants, diuretics, antitussives, or in combination with antiinflammatory agents in place of other conventional antiinflammatory agents. Can be used for co-treatment in combination with other agents previously known to be

[0046] Besides being useful for the treatment of treatment of a subject person, these methods and compounds are also mammals, rodents including pet animals, for veterinary treatment of such exotic animals and farm animals It is useful. More preferred animals include horses, dogs and cats.

Selectivity of Compounds The novel method preferably uses compounds that selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Preferably, the compound has a cyclooxygenase-2 IC _{50 of} less than about 0.5 μM and a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50.
, More preferably at least 100. Even more preferably, the compound has a cyclooxygenase-1 IC _{50 of} greater than about 5 μM. Such favorable selectivity may indicate the ability to reduce the incidence of common NSAID-induced side effects.

Pyrazoles In yet another embodiment, the present method of treating a cyclooxygenase-2 mediated disease comprises the formula II:

[0049]

[Chemical 31]

[Wherein the substituents R ⁴ , R ⁵ and R ⁶ are the compounds represented by the formula I; and pharmaceutically acceptable salts, tautomers and prodrugs thereof, respectively, It has the same definition and subdefinition as the substituents R ¹ , R ² and R ³ defined above. ] Administering to the patient a therapeutically effective amount of one or more compounds selected from the subclasses of compounds of formula I corresponding to Preferably when R ⁶ is methyl and R ⁵ is hydrogen, cyano, trifluoromethyl or ethoxycarbonyl, then R ⁴
Is not 4-bromophenyl.

[0051]   Of this subclass of compounds, the preferred group of compounds is Formula IIA or Formula IIB:

[0052]

[Chemical 32]

[Wherein, R ⁴ , R ⁵ and R ⁶ are as defined above. ] The compound represented by these; consisting of its pharmaceutically acceptable salt, a tautomer, and a prodrug.

Preferred subclasses of this compound include: 5-phenyl-1- [3-fluoro-4- (methylsulfonyl) phenyl]-
3- (trifluoromethyl) -1H-pyrazole; 5- (3-chlorophenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (4-chlorophenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3-bromophenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (4-bromophenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3-fluorophenyl) -1- [3-fluoro-4- (methylsulfoni
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (4-fluorophenyl) -1- [3-fluoro-4- (methylsulfoni
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3-methylphenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (4-methylphenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3-cyanophenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (4-cyanophenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3-trifluoromethylphenyl) -1- [3-fluoro-4- (methyl
Lusulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (4-trifluoromethylphenyl) -1- [3-fluoro-4- (methyl
5- (3-trifluoromethoxyphenyl) -1- [3-fluoro-4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole;
Cylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole
5- (4-trifluoromethoxyphenyl) -1- [3-fluoro-4- (me
Cylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole
5- (3,4-dichlorophenyl) -1- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3,4-dibromophenyl) -1- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3,4-difluorophenyl) -1- [3-fluoro-4- (methyls
Rufonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3,5-dichlorophenyl) -1- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3,5-dibromophenyl) -1- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3,5-difluorophenyl) -1- [3-fluoro-4- (methyls
Rufonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3,4-dimethylphenyl) -1- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3,5-dimethylphenyl) -1- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3-methyl-4-chlorophenyl) -1- [3-fluoro-4- (meth)
5- (4-Methyl-3-chlorophenyl) -1- [3-fluoro-4- (meth) phenylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole;
Sulfonylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3-methyl-4-fluorophenyl) -1- [3-fluoro-4- (me
Cylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole
5- (4-methyl-3-fluorophenyl) -1- [3-fluoro-4- (me
Cylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole
5- (3-methyl-4-bromophenyl) -1- [3-fluoro-4- (methyl
Lusulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (4-methyl-3-bromophenyl) -1- [3-fluoro-4- (methyl
3- (trifluoromethyl) -1H-pyrazole; 5- (3-methyl-4-trifluoromethylphenyl) -1- [3-fluoro
-4- (Methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-
Pyrazole; 5- (4-methyl-3-trifluoromethylphenyl) -1- [3-fluoro
-4- (Methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-
Pyrazole; 5- (3-methyl-4-trifluoromethoxyphenyl) -1- [3-fluor
4--4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H
-Pyrazole; 5- (4-methyl-3-trifluoromethoxyphenyl) -1- [3-fluor
4--4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H
-Pyrazole; 5- (3-cyano-4-methylphenyl) -1- [3-fluoro-4- (meth
5-sulfonyl-4-phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (4-cyano-3-methylphenyl) -1- [3-fluoro-4- (methyl
5- (3-chloro-4-methoxyphenyl) -1- [3-fluoro-4- (meth) phenylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole;
Cylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole
5- (4-chloro-3-methoxyphenyl) -1- [3-fluoro-4- (me
Cylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole
5- (2-methylpyridin-6-yl) -1- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (2-methylthiazol-4-yl) -1- [3-fluoro-4- (meth)
Lusulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (4-methylthiazol-2-yl) -1- [3-fluoro-4- (methyl
Lusulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (2-methylpyridin-3-yl) -1- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (2-methylpyridin-3-yl) -1- [3-fluoro (methylsulfo
Nyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (3-pyridinyl) -1- [3-fluoro-4- (methylsulfonyl) phenyl
5-phenyl-3- (trifluoromethyl) -1H-pyrazole; 5- (5-methylpyridin-3-yl) -1- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5- (2-methylpyridin-3-yl) -1- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 5-cyclohexyl-1- [3-fluoro-4- (methylsulfonyl) phenyl
] -3- (trifluoromethyl) -1H-pyrazole; 5-cyclopentyl-1- [3-fluoro-4- (methylsulfonyl) phenyl
]]-3- (Trifluoromethyl) -1H-pyrazole; 5-phenyl-1- [3-fluoro-4- (methylsulfonyl) phenyl]-
3- (difluoromethyl) -1H-pyrazole; 5- (3-chlorophenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (4-chlorophenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3-bromophenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (4-bromophenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3-fluorophenyl) -1- [3-fluoro-4- (methylsulfoni
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (4-fluorophenyl) -1- [3-fluoro-4- (methylsulfoni
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3-methylphenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (4-methylphenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3-cyanophenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (4-cyanophenyl) -1- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3-trifluoromethylphenyl) -1- [3-fluoro-4- (methyl
5- (4-trifluoromethylphenyl) -1- [3-fluoro-4- (methyl) phenylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole;
5- (3-trifluoromethoxyphenyl) -1- [3-fluoro-4- (methylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole;
Tyrsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (4-trifluoromethoxyphenyl) -1- [3-fluoro-4- (me
Tyrsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3,4-dichlorophenyl) -1- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3,4-dibromophenyl) -1- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3,4-difluorophenyl) -1- [3-fluoro-4- (methyls
Rufonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3,5-dichlorophenyl) -1- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3,5-dibromophenyl) -1- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3,5-difluorophenyl) -1- [3-fluoro-4- (methyls
Rufonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3,4-dimethylphenyl) -1- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3,5-dimethylphenyl) -1- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3-methyl-4-chlorophenyl) -1- [3-fluoro-4- (meth)
5- (4-methyl-3-chlorophenyl) -1- [3-fluoro-4- (methyl) phenylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole;
Sulfonylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3-methyl-4-fluorophenyl) -1- [3-fluoro-4- (me
Tyrsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (4-methyl-3-fluorophenyl) -1- [3-fluoro-4- (me
Tyrsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3-methyl-4-bromophenyl) -1- [3-fluoro-4- (meth)
Lusulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (4-methyl-3-bromophenyl) -1- [3-fluoro-4- (meth)
3- (difluoromethyl) -1H-pyrazole; 5- (3-methyl-4-trifluoromethylphenyl) -1- [3-fluoro
-4- (Methylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pi
Razole; 5- (4-methyl-3-trifluoromethylphenyl) -1- [3-fluoro
-4- (Methylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pi
Razole; 5- (3-methyl-4-trifluoromethoxyphenyl) -1- [3-fluor
4--4- (methylsulfonyl) phenyl] -3- (difluoromethyl) -1H-
Pyrazole; 5- (4-methyl-3-trifluoromethoxyphenyl) -1- [3-fluor
4--4- (methylsulfonyl) phenyl] -3- (difluoromethyl) -1H-
Pyrazole; 5- (3-cyano-4-methylphenyl) -1- [3-fluoro-4- (meth
5- (4-Cyano-3-methylphenyl) -1- [3-fluoro-4- (methyl) phenylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole;
5- (3-chloro-4-methoxyphenyl) -1- [3-fluoro-4- (meth) phenylsulfonyl] phenyl] -3- (difluoromethyl) -1H-pyrazole;
Tyrsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (4-chloro-3-methoxyphenyl) -1- [3-fluoro-4- (me
Tyrsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (2-methylpyridin-6-yl) -1- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (2-methylthiazol-4-yl) -1- [3-fluoro-4- (meth)
Lusulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (4-methylthiazol-2-yl) -1- [3-fluoro-4- (meth)
Lusulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (2-methylpyridin-3-yl) -1- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (2-methylpyridin-3-yl) -1- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (3-pyridinyl) -1- [3-fluoro-4- (methylsulfonyl) phenyl
5- (5-methylpyridin-3-yl) -1- [3-fluoro-4- (methyl)
Sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5- (2-methylpyridin-3-yl) -1- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 5-cyclohexyl-1- [3-fluoro-4- (methylsulfonyl) phenyl
] -3- (Difluoromethyl) -1H-pyrazole; 5-Cyclopentyl-1- [3-fluoro-4- (methylsulfonyl) phenyl
] -3- (Difluoromethyl) -1H-pyrazole; 1-phenyl-5- [3-fluoro-4- (methylsulfonyl) phenyl]-
3- (trifluoromethyl) -1H-pyrazole; 1- (3-chlorophenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (4-chlorophenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3-bromophenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (4-bromophenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3-fluorophenyl) -5- [3-fluoro-4- (methylsulfoni
1- (4-fluorophenyl) -5- [3-fluoro-4- (methylsulphonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole;
L) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3-methylphenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (4-methylphenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3-cyanophenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (4-cyanophenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3-trifluoromethylphenyl) -5- [3-fluoro-4- (methyl
L-sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (4-trifluoromethylphenyl) -5- [3-fluoro-4- (methyl
L-sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3-trifluoromethoxyphenyl) -5- [3-fluoro-4- (me
Cylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole
1- (4-trifluoromethoxyphenyl) -5- [3-fluoro-4- (me
Cylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole
1- (3,4-dichlorophenyl) -5- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3,4-dibromophenyl) -5- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3,4-difluorophenyl) -5- [3-fluoro-4- (methyls
Rufonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3,5-dichlorophenyl) -5- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3,5-dibromophenyl) -5- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3,5-difluorophenyl) -5- [3-fluoro-4- (methyls
Rufonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3,4-dimethylphenyl) -5- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3,5-dimethylphenyl) -5- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3-methyl-4-chlorophenyl) -5- [3-fluoro-4- (meth)
1- (4-Methyl-3-chlorophenyl) -5- [3-fluoro-4- (methyl) phenylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole;
L-sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3-methyl-4-fluorophenyl) -5- [3-fluoro-4- (me
Cylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole
1- (4-methyl-3-fluorophenyl) -5- [3-fluoro-4- (me
Cylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole
1- (3-methyl-4-bromophenyl) -5- [3-fluoro-4- (methyl
1- (4-Methyl-3-bromophenyl) -5- [3-fluoro-4- (methyl) phenyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole;
L-sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3-methyl-4-trifluoromethylphenyl) -5- [3-fluoro
-4- (Methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-
Pyrazole; 1- (4-methyl-3-trifluoromethylphenyl) -5- [3-fluoro
-4- (Methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-
Pyrazole; 1- (3-methyl-4-trifluoromethoxyphenyl) -5- [3-fluor
4--4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H
-Pyrazole; 1- (4-methyl-3-trifluoromethoxyphenyl) -5- [3-fluor
4--4- (methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H
-Pyrazole; 1- (3-cyano-4-methylphenyl) -5- [3-fluoro-4- (meth
L-sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (4-cyano-3-methylphenyl) -5- [3-fluoro-4- (meth)
L-sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3-chloro-4-methoxyphenyl) -5- [3-fluoro-4- (me
Cylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole
1- (4-chloro-3-methoxyphenyl) -5- [3-fluoro-4- (me
Cylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole
1- (2-methylpyridin-6-yl) -5- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (2-methylthiazol-4-yl) -5- [3-fluoro-4- (methyl
1- (4-Methylthiazol-2-yl) -5- [3-fluoro-4- (methyl) phenyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole;
L-sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (2-methylpyridin-3-yl) -5- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (2-methylpyridin-3-yl) -5- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (3-pyridinyl) -5- [3-fluoro-4- (methylsulfonyl) phenyl
Phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (5-methylpyridin-3-yl) -5- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1- (2-methylpyridin-3-yl) -5- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole; 1-cyclohexyl-5- [3-fluoro-4- (methylsulfonyl) phenyl
] -3- (Trifluoromethyl) -1H-pyrazole; 1-Cyclopentyl-5- [3-fluoro-4- (methylsulfonyl) phenyl
] -3- (Trifluoromethyl) -1H-pyrazole; 1-phenyl-5- [3-fluoro-4- (methylsulfonyl) phenyl]-
3- (difluoromethyl) -1H-pyrazole; 1- (3-chlorophenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (4-chlorophenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3-bromophenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (4-bromophenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3-fluorophenyl) -5- [3-fluoro-4- (methylsulfoni
1) -phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (4-fluorophenyl) -5- [3-fluoro-4- (methylsulfoni
L) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3-methylphenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (4-methylphenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3-cyanophenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (4-cyanophenyl) -5- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3-trifluoromethylphenyl) -5- [3-fluoro-4- (methyl
L-sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (4-trifluoromethylphenyl) -5- [3-fluoro-4- (methyl
L-sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3-trifluoromethoxyphenyl) -5- [3-fluoro-4- (me
1- (4-trifluoromethoxyphenyl) -5- [3-fluoro-4- (metylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole
1- (3,4-dichlorophenyl) -5- [3-fluoro-4- (methylsulfuryl) phenyl] -3- (difluoromethyl) -1H-pyrazole;
Honyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3,4-dibromophenyl) -5- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3,4-difluorophenyl) -5- [3-fluoro-4- (methyls
Rufonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3,5-dichlorophenyl) -5- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3,5-dibromophenyl) -5- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3,5-difluorophenyl) -5- [3-fluoro-4- (methyls
Rufonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3,4-dimethylphenyl) -5- [3-fluoro-4- (methylsulfur)
Honyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3,5-dimethylphenyl) -5- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3-methyl-4-chlorophenyl) -5- [3-fluoro-4- (meth)
1- (4-Methyl-3-chlorophenyl) -5- [3-fluoro-4- (methyl) phenyl) phenyl] -3- (difluoromethyl) -1H-pyrazole;
L-sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3-methyl-4-fluorophenyl) -5- [3-fluoro-4- (me
1- (4-Methyl-3-fluorophenyl) -5- [3-fluoro-4- (metylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole
1- (3-Methyl-4-bromophenyl) -5- [3-fluoro-4- (meth) (phenylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole;
1- (4-Methyl-3-bromophenyl) -5- [3-fluoro-4- (methyl) phenyl) phenyl] -3- (difluoromethyl) -1H-pyrazole;
L-sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3-methyl-4-trifluoromethylphenyl) -5- [3-fluoro
-4- (Methylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pi
Razole; 1- (4-methyl-3-trifluoromethylphenyl) -5- [3-fluoro
-4- (Methylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pi
Razole; 1- (3-methyl-4-trifluoromethoxyphenyl) -5- [3-fluor
4--4- (methylsulfonyl) phenyl] -3- (difluoromethyl) -1H-
Pyrazole; 1- (4-methyl-3-trifluoromethoxyphenyl) -5- [3-fluor
4--4- (methylsulfonyl) phenyl] -3- (difluoromethyl) -1H-
Pyrazole; 1- (3-cyano-4-methylphenyl) -5- [3-fluoro-4- (meth
L-sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (4-cyano-3-methylphenyl) -5- [3-fluoro-4- (methyl
L-sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3-chloro-4-methoxyphenyl) -5- [3-fluoro-4- (me
1- (4-chloro-3-methoxyphenyl) -5- [3-fluoro-4- (metylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole;
Tyrsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (2-pyridin-6-yl) -5- [3-fluoro-4- (methylsulfo
Nyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (2-methylthiazol-4-yl) -5- [3-fluoro-4- (meth)
1- (4-Methylthiazol-2-yl) -5- [3-fluoro-4- (methyl) phenylsulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole
Lusulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (2-methylpyridin-3-yl) -5- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (2-methylpyridin-3-yl) -5- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (3-pyridinyl) -5- [3-fluoro-4- (methylsulfonyl) phenyl
Phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (5-methylpyridin-3-yl) -5- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1- (2-methylpyridin-3-yl) -5- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -3- (difluoromethyl) -1H-pyrazole; 1-cyclohexyl-5- [3-fluoro-4- (methylsulfonyl) phenyl
] -3- (Difluoromethyl) -1H-pyrazole; 1-Cyclopentyl-5- [3-fluoro-4- (methylsulfonyl) phenyl
]]-3- (Difluoromethyl) -1H-pyrazole; 2-fluoro-4- [1-phenyl-3- (difluoromethyl) -1H-pyrazole
Zol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-chlorophenyl) -3- (difluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-chlorophenyl) -3- (difluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-bromophenyl) -3- (difluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-bromophenyl) -3- (difluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-fluorophenyl) -3- (difluoromethyi)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-fluorophenyl) -3- (difluoromethyl)
1-H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-methylphenyl) -3- (difluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-methylphenyl) -3- (difluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-cyanophenyl) -3- (difluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-cyanophenyl) -3- (difluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-trifluoromethylphenyl) -3- (dif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-trifluoromethylphenyl) -3- (dif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-trifluoromethoxymethylphenyl) -3
-(Difluoromethyl) -1H-pyrazol-5-yl] benzenesulfonami
2-fluoro-4- [1- (4-trifluoromethoxymethylphenyl) -3
-(Difluoromethyl) -1H-pyrazol-5-yl] benzenesulfonami
2-fluoro-4- [1- (3,4-dichlorophenyl) -3- (difluoro)
Methyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,4-dibromophenyl) -3- (difluoro)
Methyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,4-difluorophenyl) -3- (difluor
2-methyl-4-H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,5-dichlorophenyl) -3- (difluoro)
Methyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,5-dibromophenyl) -3- (difluoro)
Methyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,5-difluorophenyl) -3- (difluor
2-methyl-4-H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,4-dimethylphenyl) -3- (difluoro)
Methyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,5-dimethylphenyl) -3- (difluoro)
Methyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-methyl-4-chlorophenyl) -3- (dif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-methyl-3-chlorophenyl) -3- (diph
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-methyl-4-fluorophenyl) -3- (di
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-methyl-3-fluorophenyl) -3- (di
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-methyl-4-bromophenyl) -3- (dif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-Fluoro-4- [1- (4-methyl-3-bromophenyl) -3- (dif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-methyl-4-trifluoromethylphenyl))
-3- (Difluoromethyl) -1H-pyrazol-5-yl] benzenesulfone
Amido; 2-fluoro-4- [1- (4-methyl-3-trifluoromethylphenyl)
-3- (Difluoromethyl) -1H-pyrazol-5-yl] benzenesulfone
Amide; 2-fluoro-4- [1- (3-methyl-4-trifluoromethoxyphenyl)
) -3- (Difluoromethyl) -1H-pyrazol-5-yl] benzenesulfo
2-fluoro-4- [1- (4-methyl-3-trifluoromethoxyphenyl)
) -3- (Difluoromethyl) -1H-pyrazol-5-yl] benzenesulfo
2-fluoro-4- [1- (3-cyano-4-methylphenyl) -3- (diph
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-Fluoro-4- [1- (4-cyano-3-methylphenyl) -3- (dif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-chloro-4-methoxyphenyl) -3- (di
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-chloro-3-methoxyphenyl) -3- (di
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (2-methylpyridin-6-yl) -3- (diflu
Oromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (2-methylthiazol-4-yl) -3- (dif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-Fluoro-4- [1- (4-methylthiazol-2-yl) -3- (dif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (2-methylpyridin-3-yl) -3- (diflu
Oromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (2-methylpyridin-3-yl) -3- (diflu
Oromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-pyridinyl) -3- (difluoromethyl)-
1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (5-methylpyridin-3-yl) -3- (diflu
Oromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (2-methylpyridin-3-yl) -3- (diflu
Oromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1-cyclohexyl-3- (difluoromethyl) -1H
-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1-cyclopentyl-3- (difluoromethyl) -1H
-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-chlorophenyl) -3- (trifluoromethyi)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-chlorophenyl) -3- (trifluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-bromophenyl) -3- (trifluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-bromophenyl) -3- (trifluoromethyl)
1-H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-fluorophenyl) -3- (trifluorome
2H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-fluorophenyl) -3- (trifluorome)
2-Hydroxy-4- [1- (3-methylphenyl) -3- (trifluoromethy);
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-methylphenyl) -3- (trifluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-cyanophenyl) -3- (trifluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-cyanophenyl) -3- (trifluoromethyl)
) -1H-Pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-trifluoromethylphenyl) -3- (tri
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-trifluoromethylphenyl) -3- (tri
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-trifluoromethoxyphenyl) -3- (to
2-fluoro-4- [1- (4-trifluoromethoxyphenyl) -3- (tolfluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide;
Lifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,4-dichlorophenyl) -3- (trifluoro)
2-methyl-4-H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,4-dibromophenyl) -3- (trifluoro)
2-methyl-4-H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,4-difluorophenyl) -3- (triflu
Oromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,5-dichlorophenyl) -3- (trifluoro)
2-methyl-4-H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,5-dibromophenyl) -3- (trifluoro)
2-methyl-4-H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,5-difluorophenyl) -3- (triflu
Oromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,4-dimethylphenyl) -3- (trifluoro)
2-methyl-4-H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3,5-dimethylphenyl) -3- (trifluoro)
2-methyl-4-H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-methyl-4-chlorophenyl) -3- (tri
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-methyl-3-chlorophenyl) -3- (tri
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-methyl-4-fluorophenyl) -3- (to
Lifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-methyl-3-fluorophenyl) -3- (to
2-fluoro-4- [1- (3-methyl-4-bromophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide;
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-methyl-3-bromophenyl) -3- (tri
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-methyl-4-trifluoromethylphenyl)
-3- (Trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfo
2-fluoro-4- [1- (4-methyl-3-trifluoromethylphenyl)
-3- (Trifluoromethyl) -1H-pyrazol-5-yl] benzenesulfo
2-fluoro-4- [1- (3-methyl-4-trifluoromethoxyphenyl)
) -3- (Trifluoromethyl) -1H-pyrazol-5-yl] benzenesul
Honamide; 2-fluoro-4- [1- (4-methyl-3-trifluoromethoxyphenyl)
) -3- (Trifluoromethyl) -1H-pyrazol-5-yl] benzenesul
Honamide; 2-fluoro-4- [1- (3-cyano-4-methylphenyl) -3- (tri
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-cyano-3-methylphenyl) -3- (tri
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-chloro-4-methoxyphenyl) -3- (to
Lifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-chloro-3-methoxyphenyl) -3- (to
Lifluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (2-methylpyridin-6-yl) -3- (trif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (2-methylthiazol-4-yl) -3- (tri
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (4-methylthiazol-2-yl) -3- (tri
Fluoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (2-methylpyridin-3-yl) -3- (trif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (2-methylpyridin-3-yl) -3- (trif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (3-pyridinyl) -3- (trifluoromethyl)
-1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (5-methylpyridin-3-yl) -3- (trif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1- (2-methylpyridin-3-yl) -3- (trif
Luoromethyl) -1H-pyrazol-5-yl] benzenesulfonamide; 2-Fluoro-4- [1-cyclohexyl-3- (trifluoromethyl) -1
H-pyrazol-5-yl] benzenesulfonamide; 2-fluoro-4- [1-cyclopentyl-3- (trifluoromethyl) -1
H-pyrazol-5-yl] benzenesulfonamide; 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pi
Lazol-5-yl] -2-fluorobenzenesulfonamide; 4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl)
) -3- (Trifluoromethyl) -1H-pyrazol-5-yl] -2-ful
Orobenzenesulfonamide; and pharmaceutically acceptable salts, tautomers and prodrugs thereof.
However, the present invention is not limited to these.

[0055]   In one embodiment, the species is

[0056]

[Chemical 33]

And pharmaceutically acceptable salts, tautomers and prodrugs thereof. In another embodiment, the fluoro group is meta to the sulfonyl group.

[0058]   In another embodiment, the species is

[0059]

[Chemical 34]

And pharmaceutically acceptable salts, tautomers and prodrugs thereof. In another embodiment, the fluoro group is meta to the sulfonyl group.

Thiophenes In yet another embodiment, the present method of treating a cyclooxygenase-2 mediated disease comprises the formula III:

[0062]

[Chemical 35]

[Wherein the substituents R ⁷ , R ⁸ and R ⁹ are the compounds represented by the formula I; and pharmaceutically acceptable salts, tautomers and prodrugs thereof, respectively, It has the same definition and subdefinition as the substituents R ¹ , R ² and R ³ defined above. ] Administering to the patient a therapeutically effective amount of one or more compounds selected from the subclasses of compounds of formula I corresponding to

[0064]   Of this subclass of compounds, the preferred group of compounds is Formula IIIA:

[0065]

[Chemical 36]

[Wherein, R ⁷ , R ⁸ and R ⁹ are as defined above. ] The compound represented by these; consisting of its pharmaceutically acceptable salt, a tautomer, and a prodrug.

Of this subclass of compounds, another preferred group of compounds is the compound of formula III: wherein R ⁷ is cyclohexyl or phenyl, in addition to the embodiments described above for compounds of formula I. There, the cyclohexyl and phenyl, halo, cyano, C _1-2 - alkyl, C _1-2 - haloalkyl, C _1-2 - alkoxy and C _1-2 - one selected from haloalkoxy, two or Three
R ⁸ may be substituted with one group; R ⁸ is hydride, halogen, C _1-2 -alkyl, C _1-3 -alkoxy, C _1-3 —
A group selected from alkylcarbonyl, C _1-3 -haloalkyl and C _1-3 -alkoxycarbonyl. ] It consists of the compound represented by.

Of this subclass of compounds, another preferred group of compounds is the compound of formula III: wherein R ⁷ is cyclohexyl or phenyl, in addition to the embodiments described above for compounds of formula I. And said cyclohexyl and phenyl are one or two selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, fluoro, bromo and methoxy.
R ⁸ is a group selected from hydride, fluoro, chloro, bromo, iodo, cyano, methyl, methoxy, methylcarbonyl, trifluoromethyl, difluoromethyl and methoxycarbonyl. The compound represented by

Preferred species within this subclass are: 3-phenyl-4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3-chlorophenyl) -4- [3-fluoro- 4- (methylsulfonyl) phenyl] thiophene; 3- (4-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3-bromophenyl) -4- [3-fluoro -4- (methylsulfonyl) phenyl] thiophene; 3- (4-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3-fluorophenyl) -4- [3 -Fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (4-fluorophenyl) -4- [3-fluoro-4- (meth Sulfonyl) phenyl] thiophene; 3- (3-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (4-methylphenyl) -4- [3-fluoro-4- (Methylsulfonyl) phenyl] thiophene; 3- (3-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (4-cyanophenyl) -4- [3-fluoro- 4- (methylsulfonyl) phenyl] thiophene; 3- (3-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (4-trifluoromethylphenyl) -4 -[3-Fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3-trifluoromethoxyphenyl -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (4-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3 , 4-Dichlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3,4-dibromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene 3- (3,4-difluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3,5-dichlorophenyl) -4- [3-fluoro-4- (methyl Sulfonyl) phenyl] thiophene; 3- (3,5-dibromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl ]]-Thiophene; 3- (3,5-difluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3,4-dimethylphenyl) -4- [3-fluoro- 4- (methylsulfonyl) phenyl] thiophene; 3- (3,5-dimethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3-methyl-4-chlorophenyl)- 4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (4-methyl-3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3 -Methyl-4-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (4-methyl-3-phenyl) Luorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3-Methyl-4-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (4-Methyl-3-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3-Methyl-4-trifluoromethylphenyl) -4- [3- Fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (4-methyl-3-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3-methyl -4-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (4-me L-3-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3-cyano-4-methylphenyl) -4- [3-fluoro-4- ( Methylsulfonyl) phenyl] thiophene; 3- (4-cyano-3-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3-chloro-4-methoxyphenyl)- 4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (4-chloro-3-methoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- ( 2-Methylpyridin-6-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (2-methylpyridine 4-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (4-methylthiazol-2-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] Thiophene; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (2-methylpyridin-3-yl) -4- [3- Fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (3-pyridinyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (5-methylpyridin-3-yl)- 4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfo Nyl) phenyl] thiophene; 3-cyclohexyl-4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 3-cyclopentyl-4- [3-fluoro-4- (methylsulfonyl) phenyl] thiophene; 2- Fluoro-4- [4-phenyl-3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-chlorophenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- ( 4-chlorophenyl) -3-thiophenyl] benzenesulfonamide; 2-fluoro-4- [4- (3-bromophenyl) -3-thiophenyl] benzenesulfonamide; 2-fluoro-4- [4- (4-bromo) Phenyl) -3-thiophenyl] benzenesulfonamide; 2-fluoro-4- [4- 3-Fluorophenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (4-fluorophenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3- Methylphenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (4-methylphenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-cyanophenyl) ) -3-Thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (4-cyanophenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-trifluoromethylphenyl) ) -3-Thiophenyl] benzenesulfonamide; 2-fluoro-4- [4- (4-trifluoro) Methylphenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-trifluoromethoxyphenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (4- Trifluoromethoxyphenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3,4-dichlorophenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3 , 4-Dibromophenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3,4-difluorophenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3,5-Dichlorophenyl) -3-thiophenyl] benzenesulfonamide; Oro-4- [4- (3,5-dibromophenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3,5-difluorophenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3,4-dimethylphenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3,5-dimethylphenyl) -3-thiophenyl] benzenesulfone Amido; 2-Fluoro-4- [4- (3-methyl-4-chlorophenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (4-methyl-3-chlorophenyl) -3- Thiophenyl] benzenesulfonamide; 2-fluoro-4- [4- (3-methyl-4-fluorophenyl) -3-thiophenyl] 2-Fluoro-4- [4- (4-methyl-3-fluorophenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-methyl-4-bromophenyl) ) -3-Thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (4-methyl-3-bromophenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3- Methyl-4-trifluoromethylphenyl)
-3-Thiophenyl] benzenesulfonamide; 2-fluoro-4- [4- (4-methyl-3-trifluoromethylphenyl)
-2-Thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-methyl-4-trifluoromethoxyphenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (4 -Methyl-3-trifluoromethoxyphenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-cyano-4-methylphenyl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro -4- [4- (4-cyano-3-methylphenyl) -3-thiophenyl] benzenesulfonamide; 2-fluoro-4- [4- (3-chloro-4-methoxyphenyl) -3-thiophenyl] benzene Sulfonamide; 2-fluoro-4- [4- (4-chloro-3-methoxyphenyl) -3-thiophenyl 2-Fluoro-4- [4- (2-methylpyridin-6-yl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (2-methylthiazol-4-yl) ) -3-Thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (4-methylthiazol-2-yl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (2- Methylpyridin-3-yl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (2-methylpyridin-3-yl) -3-thiophenyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-Pyridinyl) -3-thiophenyl] benzenesulfonamide; 2-fluoro-4- [4- (5-methylpyridine- -Yl) -3-thiophenyl] benzenesulfonamide; 2-fluoro-4- [4- (2-methylpyridin-3-yl) -3-thiophenyl] benzenesulfonamide; 2-fluoro-4- [4-cyclohexyl -3-thiophenyl] benzenesulfonamide; 2-fluoro-4- [4-cyclopentyl-3-thiophenyl] benzenesulfonamide; and pharmaceutically acceptable salts, tautomers and prodrugs thereof. However, the present invention is not limited to these.

Isoxazoles In yet another embodiment, the method of treating a cyclooxygenase-2 mediated disease is according to formula IV:

[0071]

[Chemical 37]

[Wherein the substituents R ¹⁰ , R ¹¹ and R ¹² are compounds represented by the formula I; and pharmaceutically acceptable salts, tautomers and prodrugs thereof, respectively, It has the same definition and subdefinition as the substituents R ¹ , R ² and R ³ defined above. ] Administering to the patient a therapeutically effective amount of one or more compounds selected from the subclasses of compounds of formula I corresponding to Preferably when R ¹¹ is methyl,
R ¹⁰ is not 4-bromophenyl.

[0073]   Of this subclass of compounds, the preferred group of compounds is Formula IVA or Formula IVB:

[0074]

[Chemical 38]

[Wherein, R ¹⁰ , R ¹¹ and R ¹² are as defined above. ] The compound represented by these; consisting of its pharmaceutically acceptable salt, a tautomer, and a prodrug.

Preferred subclasses of this compound are: 3-phenyl-4- [3-fluoro-4 (methylsulfonyl) phenyl] -5
-Trifluoromethylisoxazole; 3- (3-chlorophenyl) -4- [3-fluoro-4 (methylsulfonyl)
Phenyl] -5-trifluoromethylisoxazole; 3- (4-chlorophenyl) -4- [3-fluoro-4 (methylsulfonyl)
Phenyl] -5-trifluoromethylisoxazole; 3- (3-bromophenyl) -4- [3-fluoro-4 (methylsulfonyl)
Phenyl] -5-trifluoromethylisoxazole; 3- (4-bromophenyl) -4- [3-fluoro-4 (methylsulfonyl)
Phenyl] -5-trifluoromethylisoxazole; 3- (3-fluorophenyl) -4- [3-fluoro-4 (methylsulfonyl)
) Phenyl] -5-trifluoromethylisoxazole; 3- (4-fluorophenyl) -4- [3-fluoro-4 (methylsulfonyl)
) Phenyl] -5-trifluoromethylisoxazole; 3- (3-methylphenyl) -4- [3-fluoro-4 (methylsulfonyl)
Phenyl] -5-trifluoromethylisoxazole; 3- (4-methylphenyl) -4- [3-fluoro-4 (methylsulfonyl)
Phenyl] -5-trifluoromethylisoxazole; 3- (3-cyanophenyl) -4- [3-fluoro-4 (methylsulfonyl)
Phenyl] -5-trifluoromethylisoxazole; 3- (4-cyanophenyl) -4- [3-fluoro-4 (methylsulfonyl)
Phenyl] -5-trifluoromethylisoxazole; 3- (3-trifluoromethylphenyl) -4- [3-fluoro-4 (methyl
Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (3-trifluoromethylphenyl) -4- [3-fluoro-4 (methyl
Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (4-trifluoromethylphenyl) -4- [3-fluoro-4 (methyl
Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (3-trifluoromethoxyphenyl) -4- [3-fluoro-4 (methyl
3- (4-trifluoromethoxyphenyl) -4- [3-fluoro-4 (methyl) phenyl) phenyl] -5-trifluoromethylisoxazole;
3- (3,4-dichlorophenyl) -4- [3-fluoro-4 (methylsulfol) phenyl] -5-trifluoromethylisoxazole;
Nyl) phenyl] -5-trifluoromethylisoxazole; 3- (3,4-dibromophenyl) -4- [3-fluoro-4 (methylsulfo
Nyl) phenyl] -5-trifluoromethylisoxazole; 3- (3,4-difluorophenyl) -4- [3-fluoro-4 (methylsulfur)
Phenyl) phenyl] -5-trifluoromethylisoxazole; 3- (3,5-dichlorophenyl) -4- [3-fluoro-4 (methylsulfo
Nyl) phenyl] -5-trifluoromethylisoxazole; 3- (3,5-dibromophenyl) -4- [3-fluoro-4 (methylsulfo
Nyl) phenyl] -5-trifluoromethylisoxazole; 3- (3,5-difluorophenyl) -4- [3-fluoro-4 (methylsulfur)
Phenyl) phenyl] -5-trifluoromethylisoxazole; 3- (3,4-dimethylphenyl) -4- [3-fluoro-4 (methylsulfo
Nyl) phenyl] -5-trifluoromethylisoxazole; 3- (3,5-dimethylphenyl) -4- [3-fluoro-4 (methylsulfo
Nyl) phenyl] -5-trifluoromethylisoxazole; 3- (3-methyl-4-chlorophenyl) -4- [3-fluoro-4 (methyl
Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (4-methyl-3-chlorophenyl) -4- [3-fluoro-4 (methyl
Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (3-methyl-4-fluorophenyl) -4- [3-fluoro-4 (methyl
3-sulfonyl-4-phenyl] -5-trifluoromethylisoxazole; 3- (4-methyl-3-fluorophenyl) -4- [3-fluoro-4 (meth
3-Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (3-methyl-4-bromophenyl) -4- [3-fluoro-4 (methyl
Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (4-methyl-3-bromophenyl) -4- [3-fluoro-4 (methyl
Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (3-methyl-4-trifluoromethylphenyl) -4- [3-fluoro
-4 (methylsulfonyl) phenyl] -5-trifluoromethylisoxazo
3- (4-methyl-3-trifluoromethylphenyl) -4- [3-fluoro
-4 (methylsulfonyl) phenyl] -5-trifluoromethylisoxazo
3- (3-methyl-4-trifluoromethoxyphenyl) -4- [3-fluor
Ro-4 (methylsulfonyl) phenyl] -5-trifluoromethylisoxazo
3- (4-methyl-3-trifluoromethoxyphenyl) -4- [3-fluor
Ro-4 (methylsulfonyl) phenyl] -5-trifluoromethylisoxazo
3- (3-cyano-4-methylphenyl) -4- [3-fluoro-4 (methyl
Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (4-cyano-3-methylphenyl) -4- [3-fluoro-4 (methyl
Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (3-chloro-4-methoxyphenyl) -4- [3-fluoro-4 (methyl
3-Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (4-chloro-3-methoxyphenyl) -4- [3-fluoro-4 (methyl
3-Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (2-methylpyridin-6-yl) -4- [3-fluoro-4 (methyls
Rufonyl) phenyl] -5-trifluoromethylisoxazole; 3- (2-methylthiazol-4-yl) -4- [3-fluoro-4 (methyl
Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (4-methylthiazol-2-yl) -4- [3-fluoro-4 (methyl
Sulfonyl) phenyl] -5-trifluoromethylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4 (methyls
Rufonyl) phenyl] -5-trifluoromethylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4 (methyls
Rufonyl) phenyl] -5-trifluoromethylisoxazole; 3- (3-pyridinyl) -4- [3-fluoro-4 (methylsulfonyl) phene
Nyl] -5-trifluoromethylisoxazole; 3- (5-methylpyridin-3-yl) -4- [3-fluoro-4 (methyls
Rufonyl) phenyl] -5-trifluoromethylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4 (methyls
Rufonyl) phenyl] -5-trifluoromethylisoxazole; 3-cyclohexyl-4- [3-fluoro-4 (methylsulfonyl) phenyl
] -5-Trifluoromethylisoxazole; 3-cyclopentyl-4- [3-fluoro-4 (methylsulfonyl) phenyl
] -5-Trifluoromethylisoxazole; 2-Fluoro-4- [3-phenyl-5-fluoromethylisoxazole-
4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-chlorophenyl) -5-fluoromethyliso
Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-chlorophenyl) -5-fluoromethyliso
Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-bromophenyl) -5-fluoromethyliso
Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-bromophenyl) -5-fluoromethyliso
Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-fluorophenyl) -5-fluoromethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-fluorophenyl) -5-fluoromethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methylphenyl) -5-fluoromethyliso
Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methylphenyl) -5-fluoromethyliso
Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-cyanophenyl) -5-fluoromethyliso
Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-cyanophenyl) -5-fluoromethyliso
Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethylphenyl) -5-fluor
Romethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethylphenyl) -5-fluoro
Romethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethoxyphenyl) -5-fur
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethoxyphenyl) -5-fur
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dichlorophenyl) -5-fluoromethyi;
Luisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dibromophenyl) -5-fluoromethyi;
Luisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-difluorophenyl) -5-fluorome
Tylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dichlorophenyl) -5-fluoromethyi;
Luisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dibromophenyl) -5-fluoromethyi;
Luisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-difluorophenyl) -5-fluorome
Tylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dimethylphenyl) -5-fluoromethyi;
Luisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dimethylphenyl) -5-fluoromethyi;
Luisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-chlorophenyl) -5-fluor
Romethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-chlorophenyl) -5-fluoro
Romethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-fluorophenyl) -5-fur
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-fluorophenyl) -5-fur
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-bromophenyl) -5-fluor
Romethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4-methyl-3-bromophenyl) -5-fluor
Romethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-trifluoromethylphenyl)
-5-Fluoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-trifluoromethylphenyl)
-5-Fluoromethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-trifluoromethoxyphenyl)
) -5-Fluoromethylisoxazol-4-yl] benzenesulfonamide
2-fluoro-4- [3- (4-methyl-3-trifluoromethoxyphenyl)
) -5-Fluoromethylisoxazol-4-yl] benzenesulfonamide
2-fluoro-4- [3- (3-cyano-4-methylphenyl) -5-fluoro
Romethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4-cyano-3-methylphenyl) -5-fluor
Romethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-chloro-4-methoxyphenyl) -5-fur
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-chloro-3-methoxyphenyl) -5-fur
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-6-yl) -5-fluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylthiazol-4-yl) -5-fluor
Romethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4-methylthiazol-2-yl) -5-fluor
Romethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -5-fluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -5-fluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-pyridinyl) -5-fluoromethylisooxy]
Sazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (5-methylpyridin-3-yl) -5-fluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -5-fluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3-cyclohexyl-5-fluoromethylisoxazo
2-fluoro-4- [3-cyclopentyl-5-fluoromethylisoxazo]
2-l-4-yl] benzenesulfonamide; 2-fluoro-4- [3-phenyl-5-difluoromethylisoxazole
-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-chlorophenyl) -5-difluoromethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-chlorophenyl) -5-difluoromethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-bromophenyl) -5-difluoromethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-bromophenyl) -5-difluoromethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-fluorophenyl) -5-difluoromethyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-fluorophenyl) -5-difluoromethyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methylphenyl) -5-difluoromethylii
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methylphenyl) -5-difluoromethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-cyanophenyl) -5-difluoromethylii
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-cyanophenyl) -5-difluoromethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethylphenyl) -5-diflu
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethylphenyl) -5-diful
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethoxyphenyl) -5-dif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethoxyphenyl) -5-dif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dichlorophenyl) -5-difluorome
Tyrisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dibromophenyl) -5-difluorome
Tylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-difluorophenyl) -5-difluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dichlorophenyl) -5-difluorome
Tylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dibromophenyl) -5-difluorome
Tylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-difluorophenyl) -5-difluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dimethylphenyl) -5-difluorome
Tyrisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dimethylphenyl) -5-difluorome
Tyrisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-chlorophenyl) -5-diflu
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-chlorophenyl) -5-diful
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-fluorophenyl) -5-dif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-fluorophenyl) -5-dif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-bromophenyl) -5-diflu
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-bromophenyl) -5-diflu
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-trifluoromethylphenyl)
-5-Difluoromethylisoxazol-4-yl] benzenesulfonamide
2-fluoro-4- [3- (4-methyl-3-trifluoromethylphenyl)
-5-Difluoromethylisoxazol-4-yl] benzenesulfonamide
2-fluoro-4- [3- (3-methyl-4-trifluoromethoxyphenyl)
) -5-Difluoromethylisoxazol-4-yl] benzenesulfonami
2-fluoro-4- [3- (4-methyl-3-trifluoromethoxyphenyl]
) -5-Difluoromethylisoxazol-4-yl] benzenesulfonami
2-fluoro-4- [3- (3-cyano-4-methylphenyl) -5-diflu
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-cyano-3-methylphenyl) -5-diful
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-chloro-4-methoxyphenyl) -5-dif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-chloro-3-methoxyphenyl) -5-dif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-6-yl) -5-difluor
Romethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (2-methylthiazol-4-yl) -5-diful
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methylthiazol-2-yl) -5-diflu
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (2-methylpyridin-3-yl) -5-difluor
Romethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (2-methylpyridin-3-yl) -5-difluor
Romethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-pyridinyl) -5-difluoromethylisoo]
Xazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (5-methylpyridin-3-yl) -5-difluor
Romethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (2-methylpyridin-3-yl) -5-difluor
Romethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3-cyclohexyl-5-difluoromethylisooxa]
Zol-4-yl] benzenesulfonamide; 2-fluoro-4- [3-cyclopentyl-5-difluoromethylisoxa
Zol-4-yl] benzenesulfonamide; 3-phenyl-4- [3-fluoro-4- (methylsulfonyl) phenyl]-
5-hydroxymethylisoxazole; 3- (3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-hydroxymethylisoxazole; 3- (4-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-hydroxymethylisoxazole; 3- (3-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-hydroxymethylisoxazole; 3- (4-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-hydroxymethylisoxazole; 3- (3-fluorophenyl) -4- [3-fluoro-4- (methylsulfoni
Phenyl) -5-hydroxymethylisoxazole; 3- (4-fluorophenyl) -4- [3-fluoro-4- (methylsulfoni
Phenyl) -5-hydroxymethylisoxazole; 3- (3-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-hydroxymethylisoxazole; 3- (4-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-hydroxymethylisoxazole; 3- (3-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-hydroxymethylisoxazole; 3- (4-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-hydroxymethylisoxazole; 3- (3-trifluoromethylphenyl) -4- [3-fluoro-4- (methyl
3- (4-trifluoromethylphenyl) -4- [3-fluoro-4- (methyl) phenyl) phenyl] -5-hydroxymethylisoxazole;
3- (3-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -5-hydroxymethylisoxazole;
3- (4-trifluoromethoxyphenyl) -4- [3-fluoro-4- (mehylsulfonyl) phenyl] -5-hydroxymethylisoxazole;
3- (3,4-dichlorophenyl) -4- [3-fluoro-4- (methylsulfuryl) phenyl] -5-hydroxymethylisoxazole;
Phenyl) phenyl] -5-hydroxymethylisoxazole; 3- (3,4-dibromophenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-hydroxymethylisoxazole; 3- (3,4-difluorophenyl) -4- [3-fluoro-4- (methyls
3- (3,5-dichlorophenyl) -4- [3-fluoro-4- (methylsulfuryl) phenyl] -5-hydroxymethylisoxazole;
Phenyl) phenyl] -5-hydroxymethylisoxazole; 3- (3,5-dibromophenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-hydroxymethylisoxazole; 3- (3,5-difluorophenyl) -4- [3-fluoro-4- (methyls
Rufonyl) phenyl] -5-hydroxymethylisoxazole; 3- (3,4-dimethylphenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-hydroxymethylisoxazole; 3- (3,5-dimethylphenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-hydroxymethylisoxazole; 3- (3-methyl-4-chlorophenyl) -4- [3-fluoro-4- (methyl
3- (4-Methyl-3-chlorophenyl) -4- [3-fluoro-4- (methyl) phenylsulfonyl) phenyl] -5-hydroxymethylisoxazole;
3-Sulfonyl) phenyl] -5-hydroxymethylisoxazole; 3- (3-methyl-4-fluorophenyl) -4- [3-fluoro-4- (meth
3- (4-Methyl-3-fluorophenyl) -4- [3-fluoro-4- (metylsulfonyl) phenyl] -5-hydroxymethylisoxazole;
3- (3-Methyl-4-bromophenyl) -4- [3-fluoro-4- (meth) (methylsulfonyl) phenyl] -5-hydroxymethylisoxazole;
3- (4-Methyl-3-bromophenyl) -4- [3-fluoro-4- (methyl) phenyl] phenyl] -5-hydroxymethylisoxazole;
3-sulfonyl-3-phenyl] -5-hydroxymethylisoxazole; 3- (3-methyl-4-trifluoromethylphenyl) -4- [3-fluoro
-4- (Methylsulfonyl) phenyl] -5-hydroxymethylisoxazo
3- (4-methyl-3-trifluoromethylphenyl) -4- [3-fluoro
-4- (Methylsulfonyl) phenyl] -5-hydroxymethylisoxazo
3- (3-methyl-4-trifluoromethoxyphenyl) -4- [3-fluor
4--4- (Methylsulfonyl) phenyl] -5-hydroxymethylisoxazo
3- (4-methyl-3-trifluoromethoxyphenyl) -4- [3-fluor
4--4- (Methylsulfonyl) phenyl] -5-hydroxymethylisoxazo
3- (3-cyano-4-methylphenyl) -4- [3-fluoro-4- (methyl
3-Sulfonyl) phenyl] -5-hydroxymethylisoxazole; 3- (4-cyano-3-methylphenyl) -4- [3-fluoro-4- (methyl
3-Sulfonyl) phenyl] -5-hydroxymethylisoxazole; 3- (3-chloro-4-methoxyphenyl) -4- [3-fluoro-4- (meth
3- (4-chloro-3-methoxyphenyl) -4- [3-fluoro-4- (meth) (phenylsulfonyl) phenyl] -5-hydroxymethylisoxazole;
3- (2-Methylpyridin-6-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-hydroxymethylisoxazole; 3- (2-methylthiazol-4-yl) -4- [3-fluoro-4- (methyl
3- (4-Methylthiazol-2-yl) -4- [3-fluoro-4- (meth) phenylsulfonyl) phenyl] -5-hydroxymethylisoxazole;
3-sulfonyl-2-phenyl] -5-hydroxymethylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-hydroxymethylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-hydroxymethylisoxazole; 3- (3-pyridinyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl
3-]-Hydroxymethylisoxazole; 3- (5-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-hydroxymethylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-hydroxymethylisoxazole; 3-cyclohexyl-4- [3-fluoro-4- (methylsulfonyl) phenyl
]]-5-Hydroxymethylisoxazole; 3-cyclopentyl-4- [3-fluoro-4- (methylsulfonyl) phenyl
] -5-Hydroxymethylisoxazole; 3-phenyl-4- [3-fluoro-4- (methylsulfonyl) phenyl]-
5-Fluoromethylisoxazole; 3- (3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-fluoromethylisoxazole; 3- (4-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-fluoromethylisoxazole; 3- (3-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-fluoromethylisoxazole; 3- (4-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-fluoromethylisoxazole; 3- (3-fluorophenyl) -4- [3-fluoro-4- (methylsulfoni
Phenyl) -5-fluoromethylisoxazole; 3- (4-fluorophenyl) -4- [3-fluoro-4- (methylsulfoni
) Phenyl] -5-fluoromethylisoxazole; 3- (3-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-fluoromethylisoxazole; 3- (4-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-hydroxymethylisoxazole; 3- (3-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-fluoromethylisoxazole; 3- (4-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-fluoromethylisoxazole; 3- (3-trifluoromethylphenyl) -4- [3-fluoro-4- (methyl
3- (4-trifluoromethylphenyl) -4- [3-fluoro-4- (methyl) phenyl) phenyl] -5-fluoromethylisoxazole;
3- (4-trifluoromethylphenyl) -4- [3-fluoro-4- (methyl) phenyl) phenyl] -5-fluoromethylisoxazole;
3- (3,4-dichlorophenyl) -4- [3-fluoro-4- (methylsulfuryl) phenyl] -5-fluoromethylisoxazole;
Phenyl) phenyl] -5-fluoromethylisoxazole; 3- (3,4-dibromophenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-fluoromethylisoxazole; 3- (3,4-difluorophenyl) -4- [3-fluoro-4- (methyls
Rufonyl) phenyl] -5-fluoromethylisoxazole; 3- (3,5-dichlorophenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-fluoromethylisoxazole; 3- (3,5-dibromophenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-fluoromethylisoxazole; 3- (3,5-difluorophenyl) -4- [3-fluoro-4- (methyls
Rufonyl) phenyl] -5-fluoromethylisoxazole; 3- (3,4-dimethylphenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-fluoromethylisoxazole; 3- (3,5-dimethylphenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-fluoromethylisoxazole; 3- (3-methyl-4-chlorophenyl) -4- [3-fluoro-4- (methyl
3- (4-methyl-3-chlorophenyl) -4- [3-fluoro-4- (methyl) phenylsulfonyl) phenyl] -5-fluoromethylisoxazole;
3-Sulfonyl) phenyl] -5-fluoromethylisoxazole; 3- (3-methyl-4-fluorophenyl) -4- [3-fluoro-4- (me
3- (4-Methyl-3-fluorophenyl) -4- [3-fluoro-4- (metylsulfonyl) phenyl] -5-fluoromethylisoxazole;
3- (3-Methyl-4-bromophenyl) -4- [3-fluoro-4- (meth) (methylsulfonyl) phenyl] -5-fluoromethylisoxazole;
3- (4-Methyl-3-bromophenyl) -4- [3-fluoro-4- (methyl) sulfonyl) phenyl] -5-fluoromethylisoxazole;
3-Sulfonyl) phenyl] -5-fluoromethylisoxazole; 3- (3-methyl-4-trifluoromethylphenyl) -4- [3-fluoro
-4- (Methylsulfonyl) phenyl] -5-fluoromethylisoxazole
3- (4-methyl-3-trifluoromethylphenyl) -4- [3-fluoro
-4- (Methylsulfonyl) phenyl] -5-fluoromethylisoxazole
3- (3-methyl-4-trifluoromethoxyphenyl) -4- [3-fluor
4--4- (Methylsulfonyl) phenyl] -5-fluoromethylisoxazo
3- (4-methyl-3-trifluoromethoxyphenyl) -4- [3-fluor
4--4- (Methylsulfonyl) phenyl] -5-fluoromethylisoxazo
3- (3-cyano-4-methylphenyl) -4- [3-fluoro-4- (methyl
3-Sulfonyl) phenyl] -5-fluoromethylisoxazole; 3- (4-cyano-3-methylphenyl) -4- [3-fluoro-4- (methyl
3- (3-chloro-4-methoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -5-fluoromethylisoxazole;
3- (4-chloro-3-methoxyphenyl) -4- [3-fluoro-4- (mehylsulfonyl) phenyl] -5-fluoromethylisoxazole;
3- (2-Methylpyridin-6-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-fluoromethylisoxazole; 3- (2-methylthiazol-4-yl) -4- [3-fluoro-4- (methyl
3- (4-Methylthiazol-2-yl) -4- [3-fluoro-4- (methyl) phenyl] phenyl] -5-fluoromethylisoxazole;
3-sulfonyl-2-phenyl) -5-fluoromethylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-fluoromethylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-fluoromethylisoxazole; 3- (3-pyridinyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl
3- [5-Fluoromethylisoxazole; 3- (5-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-fluoromethylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-fluoromethylisoxazole; 3-cyclohexyl-4- [3-fluoro-4- (methylsulfonyl) phenyl
] -5-Fluoromethylisoxazole; 3-cyclopentyl-4- [3-fluoro-4- (methylsulfonyl) phenyl
] -5-Fluoromethylisoxazole; 3-phenyl-3-cyclopentyl-4- [3-fluoro-4- (methylsulfo
Nyl) phenyl] -5-difluoromethylisoxazole; 3- (3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-difluoromethylisoxazole; 3- (4-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-difluoromethylisoxazole; 3- (3-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-difluoromethylisoxazole; 3- (4-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-difluoromethylisoxazole; 3- (3-fluorophenyl) -4- [3-fluoro-4- (methylsulfoni
Phenyl) -5-difluoromethylisoxazole; 3- (4-fluorophenyl) -4- [3-fluoro-4- (methylsulfoni
Phenyl) -5-difluoromethylisoxazole; 3- (3-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-difluoromethylisoxazole; 3- (4-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-difluoromethylisoxazole; 3- (3-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-difluoromethylisoxazole; 3- (4-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-difluoromethylisoxazole; 3- (3-trifluoromethylphenyl) -4- [3-fluoro-4- (methyl
3-sulfonyl-4-phenyl] -5-difluoromethylisoxazole; 3- (4-trifluoromethylphenyl) -4- [3-fluoro-4- (meth
3- (3-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -5-difluoromethylisoxazole;
3- (4-trifluoromethoxyphenyl) -4- [3-fluoro-4- (metylsulfonyl) phenyl] -5-difluoromethylisoxazole;
3- (3,4-dichlorophenyl) -4- [3-fluoro-4- (methylsulfuryl) phenyl] -5-difluoromethylisoxazole;
Phenyl) phenyl] -5-difluoromethylisoxazole; 3- (3,4-dibromophenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-difluoromethylisoxazole; 3- (3,4-difluorophenyl) -4- [3-fluoro-4- (methyls
Rufonyl) phenyl] -5-difluoromethylisoxazole; 3- (3,5-dichlorophenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-difluoromethylisoxazole; 3- (3,5-dibromophenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-difluoromethylisoxazole; 3- (3,5-difluorophenyl) -4- [3-fluoro-4- (methyls
3- (3,4-dimethylphenyl) -4- [3-fluoro-4- (methylsulfuronyl) phenyl] -5-difluoromethylisoxazole;
Phenyl) phenyl] -5-difluoromethylisoxazole; 3- (3,5-dimethylphenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-difluoromethylisoxazole; 3- (3-methyl-4-chlorophenyl) -4- [3-fluoro-4- (methyl
3- (4-Methyl-3-chlorophenyl) -4- [3-fluoro-4- (methyl) sulfonyl) phenyl] -5-difluoromethylisoxazole;
3- (3-Methyl-4-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -5-difluoromethylisoxazole;
3- (4-Methyl-3-fluorophenyl) -4- [3-fluoro-4- (metylsulfonyl) phenyl] -5-difluoromethylisoxazole;
3- (3-Methyl-4-bromophenyl) -4- [3-fluoro-4- (meth) (phenylsulfonyl) phenyl] -5-difluoromethylisoxazole;
3- (4-Methyl-3-bromophenyl) -4- [3-fluoro-4- (methyl) phenylsulfonyl) phenyl] -5-difluoromethylisoxazole;
3-Sulfonyl) phenyl] -5-difluoromethylisoxazole; 3- (3-methyl-4-trifluoromethylphenyl) -4- [3-fluoro
-4- (Methylsulfonyl) phenyl] -5-difluoromethylisoxazo
3- (4-methyl-3-trifluoromethylphenyl) -4- [3-fluoro
-4- (Methylsulfonyl) phenyl] -5-difluoromethylisoxazo
3- (3-methyl-4-trifluoromethoxyphenyl) -4- [3-fluor
4--4- (Methylsulfonyl) phenyl] -5-difluoromethylisoxazo
3- (4-methyl-3-trifluoromethoxyphenyl) -4- [3-fluor
4--4- (Methylsulfonyl) phenyl] -5-difluoromethylisoxazo
3- (3-cyano-4-methylphenyl) -4- [3-fluoro-4- (methyl
3-Sulfonyl) phenyl] -5-difluoromethylisoxazole; 3- (4-cyano-3-methylphenyl) -4- [3-fluoro-4- (methyl
3- (3-chloro-4-methoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -5-difluoromethylisoxazole;
3- (4-Chloro-3-methoxyphenyl) -4- [3-fluoro-4- (mehylsulfonyl) phenyl] -5-difluoromethylisoxazole;
3- (2-Methylpyridin-6-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-difluoromethylisoxazole; 3- (2-methylthiazol-4-yl) -4- [3-fluoro-4- (methyl
3- (4-Methylthiazol-2-yl) -4- [3-fluoro-4- (meth) phenylsulfonyl) phenyl] -5-difluoromethylisoxazole;
3-sulfonyl-2-phenyl] -5-difluoromethylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-difluoromethylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-difluoromethylisoxazole; 3- (3-pyridinyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl
3-]-Difluoromethylisoxazole; 3- (5-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-difluoromethylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-difluoromethylisoxazole; 3-cyclohexyl-4- [3-fluoro-4- (methylsulfonyl) phenyl
] -5-Difluoromethylisoxazole; 3-cyclopentyl-4- [3-fluoro-4- (methylsulfonyl) phenyl
] -5-Difluoromethylisoxazole; 3-phenyl-4- [3-fluoro-4- (methylsulfonyl) phenyl]-
5-Methylisoxazole; 3- (3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-methylisoxazole; 3- (4-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-methylisoxazole; 3- (3-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-methylisoxazole; 3- (4-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-methylisoxazole; 3- (3-fluorophenyl) -4- [3-fluoro-4- (methylsulfoni
Phenyl) -5-methylisoxazole; 3- (4-fluorophenyl) -4- [3-fluoro-4- (methylsulfoni
) Phenyl] -5-methylisoxazole; 3- (3-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-methylisoxazole; 3- (4-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-methylisoxazole; 3- (3-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-methylisoxazole; 3- (4-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl)
) Phenyl] -5-methylisoxazole; 3- (3-trifluoromethylphenyl) -4- [3-fluoro-4- (methyl
3-Sulfonyl) phenyl] -5-methylisoxazole; 3- (4-trifluoromethylphenyl) -4- [3-fluoro-4- (methyl
3- (3-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -5-methylisoxazole;
3- (4-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -5-methylisoxazole;
3- (3,4-dichlorophenyl) -4- [3-fluoro-4- (methylsulfuryl) phenyl] -5-methylisoxazole;
Phenyl) phenyl] -5-methylisoxazole; 3- (3,4-dibromophenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-methylisoxazole; 3- (3,4-difluorophenyl) -4- [3-fluoro-4- (methyls
Rufonyl) phenyl] -5-methylisoxazole; 3- (3,5-dichlorophenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-methylisoxazole; 3- (3,5-dibromophenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-methylisoxazole; 3- (3,5-difluorophenyl) -4- [3-fluoro-4- (methyls
Rufonyl) phenyl] -5-methylisoxazole; 3- (3,4-dimethylphenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-methylisoxazole; 3- (3,5-dimethylphenyl) -4- [3-fluoro-4- (methylsulfur)
Phenyl) phenyl] -5-methylisoxazole; 3- (3-methyl-4-chlorophenyl) -4- [3-fluoro-4- (methyl
3- (4-Methyl-3-chlorophenyl) -4- [3-fluoro-4- (methyl) phenyl) phenyl] -5-methylisoxazole;
3-Sulfonyl) phenyl] -5-methylisoxazole; 3- (3-methyl-4-fluorophenyl) -4- [3-fluoro-4- (me
3- (4-Methyl-3-fluorophenyl) -4- [3-fluoro-4- (metylsulfonyl) phenyl] -5-methylisoxazole;
3- (3-Methyl-4-bromophenyl) -4- [3-fluoro-4- (meth) (methylsulfonyl) phenyl] -5-methylisoxazole;
3- (4-Methyl-3-bromophenyl) -4- [3-fluoro-4- (methyl) phenylsulfonyl) phenyl] -5-methylisoxazole;
3-Sulfonyl) phenyl] -5-methylisoxazole; 3- (3-methyl-4-trifluoromethylphenyl) -4- [3-fluoro
-4- (Methylsulfonyl) phenyl] -5-methylisoxazole; 3- (4-methyl-3-trifluoromethylphenyl) -4- [3-fluoro
-4- (Methylsulfonyl) phenyl] -5-methylisoxazole; 3- (3-methyl-4-trifluoromethoxyphenyl) -4- [3-fluor
4--4- (Methylsulfonyl) phenyl] -5-methylisoxazole; 3- (4-methyl-3-trifluoromethoxyphenyl) -4- [3-fluor
4- (methylsulfonyl) phenyl] -5-methylisoxazole; 3- (3-cyano-4-methylphenyl) -4- [3-fluoro-4- (methyl
3-Sulfonyl) phenyl] -5-methylisoxazole; 3- (4-cyano-3-methylphenyl) -4- [3-fluoro-4- (methyl
3-Sulfonyl) phenyl] -5-methylisoxazole; 3- (3-chloro-4-methoxyphenyl) -4- [3-fluoro-4- (meth
3- (4-Chloro-3-methoxyphenyl) -4- [3-fluoro-4- (mehylsulfonyl) phenyl] -5-methylisoxazole;
3- (2-Methylpyridin-6-yl) -4- [3-fluoro-4- (methyl)
Sulfonyl) phenyl] -5-methylisoxazole; 3- (2-methylthiazol-4-yl) -4- [3-fluoro-4- (meth
3- (4-Methylthiazol-2-yl) -4- [3-fluoro-4- (meth) (sulfonylsulfonyl) phenyl] -5-methylisoxazole;
3-Sulfonyl) phenyl] -5-methylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-methylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-methylisoxazole; 3- (3-pyridinyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl
3-]-(5-Methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-methylisoxazole; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methyl
Sulfonyl) phenyl] -5-methylisoxazole; 3-cyclohexyl-4- [3-fluoro-4- (methylsulfonyl) phenyl
] -5-Methylisoxazole; 3-cyclopentyl-4- [3-fluoro-4- (methylsulfonyl) phenyl
2-fluoro-4- [3-phenyl-5-hydroxymethylisoxazole]
-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-chlorophenyl) -5-hydroxymethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-chlorophenyl) -5-hydroxymethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-bromophenyl) -5-hydroxymethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-bromophenyl) -5-hydroxymethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-fluorophenyl) -5-hydroxymethyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-fluorophenyl) -5-hydroxymethyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methylphenyl) -5-hydroxymethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methylphenyl) -5-hydroxymethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-cyanophenyl) -5-hydroxymethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-cyanophenyl) -5-hydroxymethylyl
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethylphenyl) -5-hydro
Xymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethylphenyl) -5-hydro
Xymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethoxyphenyl) -5-hydr
Roxymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethoxyphenyl) -5-hydr
Roxymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dichlorophenyl) -5-hydroxyl
Tyrisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dibromophenyl) -5-hydroxyl
Tylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-difluorophenyl) -5-hydroxy
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dichlorophenyl) -5-hydroxyl
Tyrisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dibromophenyl) -5-hydroxyl
Tylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-difluorophenyl) -5-hydroxy
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dimethylphenyl) -5-hydroxyl
Tyrisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dimethylphenyl) -5-hydroxyl
Tylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-chlorophenyl) -5-hydro
Xymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-chlorophenyl) -5-hydro
Xymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-fluorophenyl) -5-hydr
Roxymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-fluorophenyl) -5-hydr
Roxymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-bromophenyl) -5-hydro
Xymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-bromophenyl) -5-hydro
Xymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-trifluoromethylphenyl)
-5-Hydroxymethylisoxazol-4-yl] benzenesulfonamide
2-fluoro-4- [3- (4-methyl-3-trifluoromethylphenyl)
-5-Hydroxymethylisoxazol-4-yl] benzenesulfonamide
2-fluoro-4- [3- (3-methyl-4-trifluoromethoxyphenyl)
) -5-Hydroxymethylisoxazol-4-yl] benzenesulfonami
2-fluoro-4- [3- (4-methyl-3-trifluoromethoxyphenyl]
) -5-Hydroxymethylisoxazol-4-yl] benzenesulfonami
2-fluoro-4- [3- (3-cyano-4-methylphenyl) -5-hydro
Xymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-cyano-3-methylphenyl) -5-hydro
Xymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-chloro-4-methoxyphenyl) -5-hydr
Roxymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-chloro-3-methoxyphenyl) -5-hydr
Roxymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-6-yl) -5-hydroxy
Cimethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylthiazol-4-yl) -5-hydro
Xymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methylthiazol-2-yl) -5-hydro
Xymethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -5-hydroxy
Cimethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -5-hydroxy
Cimethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-pyridinyl) -5-hydroxymethylisoo]
Xazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (5-methylpyridin-3-yl) -5-hydroxy
Cimethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -5-hydroxy
Cimethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3-cyclohexyl-5-hydroxymethylisoxa
Zol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3-cyclopentyl-5-methylisoxazole-4
-Yl] benzenesulfonamide; 2-fluoro-4- [3-phenyl-5-methylisoxazol-4-yl
] Benzenesulfonamide; 2-fluoro-4- [3- (3-chlorophenyl) -5-methylisoxazo
2-l-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-chlorophenyl) -5-methylisoxazo
2-l-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-bromophenyl) -5-methylisoxazo
2-l-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-bromophenyl) -5-methylisoxazo
2-l-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-fluorophenyl) -5-methylisoxa
Zol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4-fluorophenyl) -5-methylisoxa
Zol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methylphenyl) -5-methylisoxazo
2-l-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methylphenyl) -5-methylisoxazo
2-l-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-cyanophenyl) -5-methylisoxazo
2-l-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-cyanophenyl) -5-methylisoxazo
2-l-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethylphenyl) -5-methyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethylphenyl) -5-methyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethoxyphenyl) -5-methyl
Luisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethoxyphenyl) -5-methyl
Luisooxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3,4-dichlorophenyl) -5-methylisoo
Xazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dibromophenyl) -5-methylisoo
Xazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-difluorophenyl) -5-methyliso
Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dichlorophenyl) -5-methylisoo
Xazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dibromophenyl) -5-methylisoo
Xazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-difluorophenyl) -5-methyliso
Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dimethylphenyl) -5-methylisoo
Xazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dimethylphenyl) -5-methylisoo
Xazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-chlorophenyl) -5-methyl
Isoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4-methyl-3-chlorophenyl) -5-methyl
Isoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-fluorophenyl) -5-methyl
Luisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-fluorophenyl) -5-methyi;
Luisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-bromophenyl) -5-methyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-bromophenyl) -5-methyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-trifluoromethylphenyl)
-5-Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-trifluoromethylphenyl)
-5-Methylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-trifluoromethoxyphenyl)
) -5-Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-trifluoromethoxyphenyl)
) -5-Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-cyano-4-methylphenyl) -5-methyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-cyano-3-methylphenyl) -5-methyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-chloro-4-methoxyphenyl) -5-methyi;
Luisooxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4-chloro-3-methoxyphenyl) -5-methyl
Luisooxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (2-methylpyridin-6-yl) -5-methylyl
Sooxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (2-methylthiazol-4-yl) -5-methyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methylthiazol-2-yl) -5-methyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -5-methylii
Sooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -5-methylyl
Soxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-pyridinyl) -5-methylisoxazole
-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -5-methylyl
Sooxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3-cyclohexyl-5-methylisoxazole-4
-Yl] benzenesulfonamide; 2-fluoro-4- [3-cyclopentyl-5-methylisoxazole-4
-Yl] benzenesulfonamide; 2-fluoro-4- [3-phenyl-5-trifluoromethylisoxazo
Lu-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-chlorophenyl) -5-trifluoromethyl
Isoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4-chlorophenyl) -5-trifluoromethyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-bromophenyl) -5-trifluoromethyl
Isoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4-bromophenyl) -5-trifluoromethyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-fluorophenyl) -5-trifluoromethyi;
Luisooxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-fluorophenyl) -5-trifluoromethyi;
Luisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methylphenyl) -5-trifluoromethyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methylphenyl) -5-trifluoromethyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-cyanophenyl) -5-trifluoromethyl
Isoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-cyanophenyl) -5-trifluoromethyl
Isoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-trifluoromethylphenyl) -5-trif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethylphenyl) -5-trif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethoxyphenyl) -5-tri
Fluoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethoxyphenyl) -5-tri
Fluoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dichlorophenyl) -5-trifluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dibromophenyl) -5-trifluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-difluorophenyl) -5-trifluoro
Romethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dichlorophenyl) -5-trifluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dibromophenyl) -5-trifluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-difluorophenyl) -5-trifluoro
Romethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dimethylphenyl) -5-trifluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dimethylphenyl) -5-trifluoro
Methylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-chlorophenyl) -5-trif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-chlorophenyl) -5-trif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-fluorophenyl) -5-tri
Fluoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-fluorophenyl) -5-tri
Fluoromethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-bromophenyl) -5-trif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-bromophenyl) -5-trif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-trifluoromethylphenyl)
-5-Trifluoromethylisoxazol-4-yl] benzenesulfonami
2-fluoro-4- [3- (4-methyl-3-trifluoromethylphenyl)
-5-Trifluoromethylisoxazol-4-yl] benzenesulfonami
2-fluoro-4- [3- (3-methyl-4-trifluoromethoxyphenyl]
) -5-Trifluoromethylisoxazol-4-yl] benzenesulfon
Mido; 2-fluoro-4- [3- (4-methyl-3-trifluoromethoxyphenyl)
) -5-Trifluoromethylisoxazol-4-yl] benzenesulfon
Mido; 2-fluoro-4- [3- (3-cyano-4-methylphenyl) -5-trif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-cyano-3-methylphenyl) -5-trif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-chloro-4-methoxyphenyl) -5-tri
Fluoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-chloro-3-methoxyphenyl) -5-tri
Fluoromethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (2-methylpyridin-6-yl) -5-triflu
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (2-methylthiazol-4-yl) -5-trif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methylthiazol-2-yl) -5-trif
Luoromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -5-triflu
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -5-triflu
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-pyridinyl) -5-trifluoromethyliso
Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (5-methylpyridin-3-yl) -5-triflu
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -5-triflu
Oromethylisoxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3-cyclohexyl-5-trifluoromethylisooxy]
Sazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3-cyclopentyl-5-trifluoromethylisooxy]
Sazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3-phenyl-5-methyl-4-isoxazolyl] be
And pharmaceutically acceptable salts, tautomers and prodrugs thereof.
However, the present invention is not limited to these.

[0077]   In one embodiment, the species is

[0078]

[Chemical Formula 39]

And pharmaceutically acceptable salts, tautomers and prodrugs thereof. In another embodiment, the fluoro group is meta to the sulfonyl group.

[0080]   In another embodiment, the species is

[0081]

[Chemical 40]

And pharmaceutically acceptable salts, tautomers and prodrugs thereof. In another embodiment, the fluoro group is meta to the sulfonyl group.

Furanones In yet another embodiment, the method of treating a cyclooxygenase-2 mediated disease is according to formula V:

[0084]

[Chemical 41]

[Wherein the substituents R ¹³ , R ¹⁴ and R ¹⁵ are each a compound represented by the formula I; and pharmaceutically acceptable salts, tautomers and prodrugs thereof, respectively, It has the same definition and subdefinition as the substituents R ¹ , R ² and R ³ defined above. ] Administering to the patient a therapeutically effective amount of one or more compounds selected from the subclasses of compounds of formula I corresponding to Preferably, when R ¹⁴ is hydrogen, R ¹³ is not 4-bromophenyl.

[0086]   Of this subclass of compounds, the preferred group of compounds is Formula VA or Formula VB:

[0087]

[Chemical 42]

[Wherein, R ¹³ , R ¹⁴ and R ¹⁵ are as defined above. ] It consists of the compound represented by these; those pharmaceutically acceptable salt, a tautomer, and a prodrug.

Preferred subclasses of this compound include: 2-fluoro-4- [4-5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4 -(3-chlorophenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (4-chlorophenyl) -5-oxo-2,5-dihydro- 2-Fluoro-4- [4- (3-bromophenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro-4- [4 -(4-Bromophenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (3-fluorophenyl) -5 -Oxo-2,5-
Dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (4-fluorophenyl) -5-oxo-2,5-
2-Hydroxy-4-furanyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-methylphenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro-4- [4- (4-Methylphenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (3-cyanophenyl) -5-oxo-2, 5-Dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro-4- [4- (4-cyanophenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro- 4- [4- (3-trifluoromethylphenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4 (4-Trifluoromethylphenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-trifluoromethoxyphenyl) -5-oxo-2 , 5-Dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro-4- [4- (4-trifluoromethoxyphenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2 -Fluoro-4- [4- (3,4-dichlorophenyl) -5-oxo-2,
5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (3,4-dibromophenyl) -5-oxo-2,
5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (3,4-difluorophenyl) -5-oxo-2
, 5-Dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (3,5-dichlorophenyl) -5-oxo-2,
5-Dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (3,5-dibromophenyl) -5-oxo-2,
5-Dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (3,5-difluorophenyl) -5-oxo-2
, 5-Dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (3,4-dimethylphenyl) -5-oxo-2,
5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (3,5-dimethylphenyl) -5-oxo-2,
5-Dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-methyl-4-chlorophenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2 -Fluoro-4- [4- (4-methyl-3-chlorophenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-methyl- 4-fluorophenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (4-methyl-3-fluorophenyl) -5-oxo-2, 5-Dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (3-methyl-4-bromophenyl) -5-oxo-2,5-dihydro-3- Ranyl] benzenesulfonamide; 2-Fluoro-4- [4- (4-methyl-3-bromophenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-methyl-4-trifluoromethylphenyl)
-5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (4-methyl-3-trifluoromethylphenyl)
-5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (3-methyl-4-trifluoromethoxyphenyl) -5-oxo-2,5-dihydro -2-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (4-methyl-3-trifluoromethoxyphenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2 -Fluoro-4- [4- (3-cyano-4-methylphenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro-4- [4- (4-cyano -3-Methylphenyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (3-chloro-4-methoxyphenyl) Nil) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (4-chloro-3-methoxyphenyl) -5-oxo-2,5-dihydro -3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (2-methylpyridin-6-yl) -5-oxo-
2,5-Dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro-4- [4- (2-methylthiazol-4-yl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfone Amido; 2-Fluoro-4- [4- (4-methylthiazol-2-yl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro-4- [4- ( 2-Methylpyridin-3-yl) -5-oxo-
2,5-Dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (2-methylpyridin-3-yl) -5-oxo-
2,5-Dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro-4- [4- (3-pyridinyl) -5-oxo-2,5-dihydro-3-furanyl] benzenesulfonamide; 2-Fluoro -4- [4- (5-methylpyridin-3-yl) -5-oxo-
2,5-Dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4- (2-methylpyridin-3-yl) -5-oxo-
2,5-dihydro-3-furanyl] benzenesulfonamide; 2-fluoro-4- [4-cyclohexyl-5-oxo-2,5-dihydro-
3-furanyl] benzenesulfonamide; 2-fluoro-4- [4-cyclopentyl-5-oxo-2,5-dihydro-
3-furanyl] benzenesulfonamide; 3-phenyl-4- [3-fluoro-4- (methylsulfonyl) phenyl]-
2- (5H) -furanone; 3- (3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4-chlorophenyl) -4- [3 -Fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3-Bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone 3- (4-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3-fluorophenyl) -4- [3-fluoro-4; -(Methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3-Methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4-methylphenyl) -4- [3-fluoro-4- (Methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4 -Cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3-trifluoromethylphenyl) -4- [3-fluoro-4- (methyl Sulfonyl) phenyl] -2 (5H) -furanone; 3- (4-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3 (3-Trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4-trifluoromethoxyphenyl) -4- [3-fluoro- 4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3,4-dichlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3 -(3,4-Dibromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3,4-difluorophenyl) -4- [3-fluoro -4- (Methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3,5-dichlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3,5-dibromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3,5-difluoro Phenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3,4-dimethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) Phenyl] -2 (5H) -furanone; 3- (3,5-dimethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3-methyl -4-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4-methyl-3-chlorophenyl) -4- [3-fluoro-4- (Met Sulfonyl) phenyl] -2 (5H) -furanone; 3- (3-Methyl-4-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4-Methyl-3-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3-methyl-4-bromophenyl) -4- [ 3-Fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4-Methyl-3-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3-methyl-4-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4 Methyl-3-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3-Methyl-4-trifluoromethoxyphenyl) -4- [3-Fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4-Methyl-3-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl ] -2 (5H) -Furanone; 3- (3-Cyano-4-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4- Cyano-3-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3-chloro-4-methoxyphenyl)- -[3-Fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4-chloro-3-methoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (2-methylpyridin-6-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (2-methyl Thiazol-4-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (4-methylthiazol-2-yl) -4- [3-fluoro- 4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H)- Furanone 3- (2-Methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (3-pyridinyl) -4- [3- Fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (5-methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H ) -Furanone; 3- (2-Methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3- (2-Methylpyridin-3-) Yl) -4- [3-Fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 3-cyclohexyl-4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -Furano 3-Cyclopentyl-4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone; 4- [3-Fluoro-4- (methylsulfonyl) phenyl] -2 (5H) -furanone And, pharmaceutically acceptable salts, tautomers and prodrugs thereof, but are not limited thereto.

[0090]   In one embodiment, the species is

[0091]

[Chemical 43]

And pharmaceutically acceptable salts, tautomers and prodrugs thereof. In another embodiment, the fluoro group is meta to the sulfonyl group.

Cyclopentenes In yet another embodiment, the method of treating a cyclooxygenase-2 mediated disease is of formula VI:

[0094]

[Chemical 44]

[Wherein the substituents R ¹⁶ , R ¹⁷ and R ¹⁸ are the compounds represented by formula I; and pharmaceutically acceptable salts, tautomers and prodrugs thereof, respectively, It has the same definition and subdefinition as the substituents R ¹ , R ² and R ³ defined above. ] Administering to the patient a therapeutically effective amount of one or more compounds selected from the subclasses of compounds of formula I corresponding to

[0096]   Within this subclass of compounds, a preferred group of compounds is Formula VIA:

[0097]

[Chemical formula 45]

[Wherein, R ¹⁶ , R ¹⁷ and R ¹⁸ are as defined above. ] The compound represented by these; consisting of its pharmaceutically acceptable salt, a tautomer, and a prodrug.

Preferred species of this subclass are: 2-fluoro-4- [2-phenylcyclopenten-1-yl] benzenesulfonamide; 2-fluoro-4- [2- (3-chlorophenyl) cyclopentene- 1-yl] benzenesulfonamide; 2-fluoro-4- [2- (4-chlorophenyl) cyclopenten-1-yl] benzenesulfonamide; 2-fluoro-4- [2- (3-bromophenyl) cyclopentene-1 2-yl-4-benzenesulfonamide; 2-fluoro-4- [2- (4-bromophenyl) cyclopenten-1-yl] benzenesulfonamide; 2-fluoro-4- [2- (3-fluorophenyl) cyclopentene-1 -Yl] benzenesulfonamide; 2-fluoro-4- [2- (4-fluorophenyl) Clopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (3-methylphenyl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (4-methylphenyl) Cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (3-cyanophenyl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (4-cyanophenyl) Cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (3-trifluoromethylphenyl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (4-tri Fluoromethylphenyl) cyclopenten-1-yl] benzenesulfonamide; 2-fluoro 4- [2- (3-trifluoromethoxyphenyl) cyclopenten-1-yl] benzenesulfonamide; 2-fluoro-4- [2- (4-trifluoromethoxyphenyl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (3,4-dichlorophenyl) cyclopentene-1
-Yl] benzenesulfonamide; 2-fluoro-4- [2- (3,4-dibromophenyl) cyclopentene-1
-Yl] benzenesulfonamide; 2-fluoro-4- [2- (3,4-difluorophenyl) cyclopentene-
1-yl] benzenesulfonamide; 2-fluoro-4- [2- (3,5-dichlorophenyl) cyclopentene-1
-Yl] benzenesulfonamide; 2-fluoro-4- [2- (3,5-dibromophenyl) cyclopentene-1
-Yl] benzenesulfonamide; 2-fluoro-4- [2- (3,5-difluorophenyl) cyclopentene-
1-yl] benzenesulfonamide; 2-fluoro-4- [2- (3,4-dimethylphenyl) cyclopentene-1
-Yl] benzenesulfonamide; 2-fluoro-4- [2- (3,5-dimethylphenyl) cyclopentene-1
2-yl-4-benzenesulfonamide; 2-fluoro-4- [2- (3-methyl-4-chlorophenyl) cyclopenten-1-yl] benzenesulfonamide; 2-fluoro-4- [2- (4-methyl-3) -Chlorophenyl) cyclopenten-1-yl] benzenesulfonamide; 2-fluoro-4- [2- (3-methyl-4-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide; 2-fluoro-4- [2 -(4-Methyl-3-fluorophenyl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (3-methyl-4-bromophenyl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (4-methyl-3-bromophenyl) cyclopenten-1-yl] be Zen sulfonamide; 2-fluoro-4- [2- (3-methyl-4-trifluoromethylphenyl)
Cyclopenten-1-yl] benzenesulfonamide; 2-fluoro-4- [2- (4-methyl-3-trifluoromethylphenyl)
Cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (3-methyl-4-trifluoromethoxyphenyl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (3-Methyl-4-trifluoromethoxyphenyl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (3-cyano-4-methylphenyl) cyclopenten-1-yl] benzenesulfonamide 2-Fluoro-4- [2- (4-cyano-3-methylphenyl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (3-chloro-4-methoxyphenyl) cyclopentene -1-yl] benzenesulfonamide; 2-fluoro-4- [2- (4-chloro-3- Toxyphenyl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (2-methylpyridin-6-yl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2 -(4-Methylpyridin-2-yl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (2-methylpyridin-3-yl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (2-methylpyridin-3-yl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2- (3-pyridinyl) cyclopenten-1-yl] benzene Sulfonamide; 2-fluoro-4- [2- (5-methylpyridin-3-yl) cyclopenten-1-i ] Benzenesulfonamide; 2-Fluoro-4- [2- (2-methylpyridin-3-yl) cyclopenten-1-yl] benzenesulfonamide; 2-Fluoro-4- [2-cyclohexylcyclopenten-1-yl] Benzenesulfonamide; 2-Fluoro-4- [2-cyclopentylcyclopenten-1-yl] benzenesulfonamide; 4- [2-phenylcyclopenten-1-yl] -2-fluorophenylmethylsulfone; 4- [2- ( 3-chlorophenyl) cyclopenten-1-yl] -2-fluorophenylmethylsulfone; 4- [2- (4-chlorophenyl) cyclopenten-1-yl] -2-fluorophenylmethylsulfone; 4- [2- (3- Bromophenyl) cyclopenten-1-yl] -2-fluorophenyl Methyl sulfone; 4- [2- (4-Bromophenyl) cyclopenten-1-yl] -2-fluorophenylmethyl sulfone; 4- [2- (3-Fluorophenyl) cyclopenten-1-yl] -2-fluorophenyl Methyl sulfone; 4- [2- (4-Fluorophenyl) cyclopenten-1-yl] -2-fluorophenylmethyl sulfone; 4- [2- (3-Methylphenyl) cyclopenten-1-yl] -2-fluorophenyl Methyl sulfone; 4- [2- (3-Methylphenyl) cyclopenten-1-yl] -2-fluorophenylmethyl sulfone; 4- [2- (3-Cyanophenyl) cyclopenten-1-yl] -2-fluorophenyl Methyl sulfone; 4- [2- (4-cyanophenyl) cyclopenten-1-yl] -2- Le Oro methyl sulfone; 4- [2- (3-trifluoromethylphenyl) cyclopenten-1-yl]
2-Fluorophenylmethylsulfone; 4- [2- (4-trifluoromethylphenyl) cyclopenten-1-yl]
2- [2- (3-trifluoromethoxyphenyl) cyclopenten-1-yl] -2-fluorophenylmethylsulfone; 4- [2- (4-trifluoromethoxyphenyl) cyclopentene- 1-yl] -2-fluorophenylmethyl sulfone; 4- [2- (3,4-dichlorophenyl) cyclopenten-1-yl] -2-
Fluorophenyl methyl sulfone; 4- [2- (3,4-dibromophenyl) cyclopenten-1-yl] -2-
Fluorophenyl methyl sulfone; 4- [2- (3,4-difluorophenyl) cyclopenten-1-yl] -2
-Fluorophenylmethyl sulfone; 4- [2- (3,5-dichlorophenyl) cyclopenten-1-yl] -2-
Fluorophenyl methyl sulfone; 4- [2- (3,5-dibromophenyl) cyclopenten-1-yl] -2-
Fluorophenyl methyl sulfone; 4- [2- (3,5-difluorophenyl) cyclopenten-1-yl] -2
-Fluorophenylmethyl sulfone; 4- [2- (3,4-dimethylphenyl) cyclopenten-1-yl] -2-
Fluorophenyl methyl sulfone; 4- [2- (3,4-dimethylphenyl) cyclopenten-1-yl] -2-
Fluorophenyl methyl sulfone; 4- [2- (3,5-dimethylphenyl) cyclopenten-1-yl] -2-
Fluorophenyl methyl sulfone; 4- [2- (3-methyl-4-chlorophenyl) cyclopenten-1-yl]
2-fluorophenylmethyl sulfone; 4- [2- (4-methyl-3-chlorophenyl) cyclopenten-1-yl]
2- [2- (3-Methyl-4-fluorophenyl) cyclopenten-1-yl] -2-fluorophenylmethylsulfone; 4- [2- (4-methyl-3-fluoro) Phenyl) cyclopenten-1-yl] -2-fluorophenylmethylsulfone; 4- [2- (3-methyl-4-bromophenyl) cyclopenten-1-yl]
2-fluorophenylmethyl sulfone; 4- [2- (4-methyl-3-bromophenyl) cyclopenten-1-yl]
2- [2- (3-methyl-4-trifluoromethylphenyl) cyclopenten-1-yl] -2-fluorophenylmethyl sulfone; 4- [2- (4-methyl-3) -Trifluoromethylphenyl) cyclopenten-1-yl] -2-fluorophenylmethylsulfone; 4- [2- (3-methyl-4-trifluoromethoxyphenyl) cyclopenten-1-yl] -2-fluorophenylmethylsulfone 4- [2- (4-Methyl-3-trifluoromethoxyphenyl) cyclopenten-1-yl] -2-fluorophenylmethylsulfone; 4- [2- (3-cyano-4-methylphenyl) cyclopentene-1 -Ill]
2-Fluorophenylmethylsulfone; 4- [2- (4-cyano-3-methylphenyl) cyclopenten-1-yl]
2- [2- (3-chloro-4-methoxyphenyl) cyclopenten-1-yl] -2-fluorophenylmethylsulfone; 4- [2- (4-chloro-3-methoxy) Phenyl) cyclopenten-1-yl] -2-fluorophenylmethylsulfone; 4- [2- (2-methylpyridin-6-yl) cyclopenten-1-yl]-
2-fluorophenylmethyl sulfone; 4- [2- (2-methylthiazol-4-yl) cyclopenten-1-yl]
2-fluorophenylmethyl sulfone; 4- [2- (4-methylthiazol-2-yl) cyclopenten-1-yl]
2-Fluorophenylmethylsulfone; 4- [2- (2-methylpyridin-3-yl) cyclopenten-1-yl]-
2-Fluorophenylmethylsulfone; 4- [2- (2-methylpyridin-3-yl) cyclopenten-1-yl]-
2- [2- (3-pyridinyl) cyclopenten-1-yl] -2-fluorophenylmethylsulfone; 4- [2- (5-methylpyridin-3-yl) cyclopentene-1- Il-
2-Fluorophenylmethylsulfone; 4- [2- (2-methylpyridin-3-yl) cyclopenten-1-yl]-
2- [2-cyclohexylcyclopenten-1-yl] -2-fluorophenylmethylsulfone; 4- [2-cyclopentylcyclopenten-1-yl] -2-fluorophenylmethylsulfone; 2- ( 3,5-difluorophenyl) -3- (3-fluoro-4- (methylsulfonyl) -2-cyclopenten-1-one; and their pharmaceutically acceptable salts, tautomers and prodrugs However, the present invention is not limited to these.

[0100]   In one embodiment, the species is

[0101]

[Chemical formula 46]

And pharmaceutically acceptable salts, tautomers and prodrugs thereof. In another embodiment, the fluoro group is meta to the sulfonyl group.

Pyridines In yet another embodiment, the method of treating a cyclooxygenase-2 mediated disease is according to formula VII:

[0104]

[Chemical 47]

[Wherein the substituents R ¹⁹ , R ²⁰ and R ²¹ are the compounds represented by the formula I; and pharmaceutically acceptable salts, tautomers and prodrugs thereof, respectively, It has the same definition and subdefinition as the substituents R ¹ , R ² and R ³ defined above. ] Administering to the patient a therapeutically effective amount of one or more compounds selected from the subclasses of compounds of formula I corresponding to

[0106]   Within this subclass of compounds, a preferred group of compounds is Formula VIIA:

[0107]

[Chemical 48]

[Wherein, R ¹⁹ , R ²⁰ and R ²¹ are as defined above. ] The compound represented by these; consisting of its pharmaceutically acceptable salt, a tautomer, and a prodrug.

Preferred species within this subclass are: 2-fluoro-4- [3-phenyl-3-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (3-chlorophenyl) -3. 2-Pyridinyl] -benzene-sulfonamide; 2-Fluoro-4- [3- (4-chlorophenyl) -3-pyridinyl] -benzene-sulfonamide; 2-Fluoro-4- [3- (3-bromophenyl)- 3-Pyridinyl] -benzene-sulfonamide; 2-Fluoro-4- [3- (4-bromophenyl) -3-pyridinyl] -benzene-sulfonamide; 2-Fluoro-4- [3- (3-fluorophenyl) ) -3-Pyridinyl] -benzene-sulfonamide; 2-fluoro-4- [3- (4-fluorophenyl) -3-pyridinyl] -benze -Sulfonamide; 2-fluoro-4- [3- (3-methylphenyl) -3-pyridinyl] -benzene-sulfonamide; 2-Fluoro-4- [3- (4-methylphenyl) -3-pyridinyl] 2-benzene-4-sulfonamide; 2-fluoro-4- [3- (3-cyanophenyl) -3-pyridinyl] -benzene-sulfonamide; 2-fluoro-4- [3- (4-cyanophenyl) -3- Pyridinyl] -benzene-sulfonamide; 2-Fluoro-4- [3- (3-trifluoromethylphenyl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (4-trifluoromethyl) Phenyl) -3-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethoxyphenyl) -3-pyri 2-fluoro-4- [3- (4-trifluoromethoxyphenyl) -3-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (3,4-dichlorophenyl] ) -3-Pyridinyl]
-Benzenesulfonamide; 2-fluoro-4- [3- (3,4-dibromophenyl) -3-pyridinyl]
-Benzenesulfonamide; 2-fluoro-4- [3- (3,4-difluorophenyl) -3-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (3,5-dichlorophenyl) -3. -Pyridinyl]
-Benzene-sulfonamide; 2-fluoro-4- [3- (3,5-dibromophenyl) -3-pyridinyl]
-Benzenesulfonamide; 2-fluoro-4- [3- (3,5-difluorobromophenyl) -3-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (3,4-dimethylphenyl) -3-Pyridinyl]
-Benzenesulfonamide; 2-fluoro-4- [3- (3,5-dimethylphenyl) -3-pyridinyl]
-Benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-chlorophenyl) -3-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-chlorophenyl) ) -3-Pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-fluorophenyl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- ( 4-Methyl-3-fluorophenyl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-bromophenyl) -3-pyridinyl] -benzenesulfonamide; 2- Fluoro-4- [3- (4-methyl-3-bromophenyl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [ 3- (3-methyl-4-trifluoromethylphenyl)
-3-Pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (4-methyl-3-trifluoromethylphenyl)
-2-Pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-trifluoromethoxyphenyl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-Methyl-4-trifluoromethoxyphenyl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (4-methyl-3-trifluoromethoxyphenyl) -3-pyridinyl] -benzene 2-fluoro-4- [3- (3-cyano-4-methylphenyl) -3-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (4-cyano-3-methylphenyl) ) -3-Pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-chloro-4-methoxyphenyl) -3- Lydinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (4-chloro-3-methoxyphenyl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (2-methylpyridine) -6-yl) -3-Pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (2-methylthiazol-4-yl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (4-Methylthiazol-2-yl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (2-methylpyridin-3-yl) -3-pyridinyl] -benzenesulfone Amido; 2-Fluoro-4- [3- (2-methylpyridin-3-yl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro-4 [3- (3-Pyridinyl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (5-methylpyridin-3-yl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro -4- [3- (2-Methylpyridinyl-4-yl) -3-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3-cyclohexyl-3-pyridinyl] -benzene-sulfonamide; 2-Fluoro- 4- [3-Cyclopentyl-3-pyridinyl] -benzene-sulfonamide; 2-Fluoro-4- [3-phenyl-2-pyridinyl] -benzene-sulfonamide; 2-Fluoro-4- [3- (3- 2-Chlorophenyl) -2-pyridinyl] -benzene-sulfonamide; 2-fluoro-4- [3- (4-chlorophenyl) -2- Lydinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-bromophenyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (4-bromophenyl) -2- Pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-fluorophenyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (4-fluorophenyl) -2- Pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-methylphenyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (4-methylphenyl) -2- Pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-cyanophenyl) -2-pyridinyl] -benzenesulfon Amido; 2-Fluoro-4- [3- (4-cyanophenyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-trifluoromethylphenyl) -2-pyridinyl]- Benzenesulfonamide; 2-Fluoro-4- [3- (4-trifluoromethylphenyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-trifluoromethoxyphenyl) -2 2-Pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (4-trifluoromethoxyphenyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3,4-dichlorophenyl) ) -2-Pyridinyl]
-Benzenesulfonamide; 2-fluoro-4- [3- (3,4-dibromophenyl) -2-pyridinyl]
-Benzenesulfonamide; 2-fluoro-4- [3- (3,4-difluorophenyl) -2-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (3,5-dichlorophenyl) -2. -Pyridinyl]
-Benzenesulfonamide; 2-fluoro-4- [3- (3,5-dibromophenyl) -2-pyridinyl]
-Benzenesulfonamide; 2-fluoro-4- [3- (3,5-difluorophenyl) -2-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (3,4-dimethylphenyl)- 2-pyridinyl]
-Benzenesulfonamide; 2-fluoro-4- [3- (3,5-dimethylphenyl) -2-pyridinyl]
-Benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-chlorophenyl) -2-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-chlorophenyl) ) -2-Pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-fluorophenyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- ( 4-Methyl-3-fluorophenyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-bromophenyl) -2-pyridinyl] -benzenesulfonamide; 2- Fluoro-4- [3- (4-methyl-3-bromophenyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [ 3- (3-methyl-4-trifluoromethylphenyl)
2-Pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-trifluoromethylphenyl)
2-Pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-trifluoromethoxyphenyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (4-Methyl-3-trifluoromethoxyphenyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-cyano-4-methylphenyl) -2-pyridinyl] -benzenesulfonamide 2-Fluoro-4- [3- (4-cyano-3-methylphenyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (3-chloro-4-methoxyphenyl)- 2-Pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (4-chloro-3-methoxyphenyl) -2-pyridinyl] 2-Fluoro-4- [3- (2-methylpyridin-6-yl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (2-methylthiazole-4-) 2-fluoro-4- [3- (4-methylthiazol-2-yl) -2-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (2-Methylpyridin-3-yl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (2-methylpyridin-3-yl) -2-pyridinyl] -benzenesulfonamide; 2 -Fluoro-4- [3- (3-pyridinyl) -2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3- (5-methylpyridine- 2-yl) -2-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -2-pyridinyl] -benzenesulfonamide; 2-fluoro-4- [3 -Cyclohexyl-2-pyridinyl] -benzenesulfonamide; 2-Fluoro-4- [3-cyclopentyl-2-pyridinyl] -benzenesulfonamide; 4- [3-Phenyl-2-pyridinyl] -2-fluorophenylmethylsulfone 4- [3- (3-chlorophenyl) -2-pyridinyl] -2-fluorophenylmethylsulfone; 4- [3- (4-chlorophenyl) -2-pyridinyl] -2-fluorophenylmethylsulfone; 4- [ 3- [3-Bromophenyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [ 3- [4-Bromophenyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (3-fluorophenyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (4-fluorophenyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (3-methylphenyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (4 -Methylphenyl) -2-pyridinyl] -2-fluorophenylmethylsulfone; 4- [3- (3-cyanophenyl) -2-pyridinyl] -2-fluorophenylmethylsulfone; 4- [3- (4-cyano Phenyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (3-trifluoromethylphenyl) -2 -Pyridinyl] -2-fluorophenylmethylsulfone; 4- [3- (4-trifluoromethylphenyl) -2-pyridinyl] -2-fluorophenylmethylsulfone; 4- [3- (3-trifluoromethoxyphenyl) -2-Pyridinyl] -2-
Fluorophenyl methyl sulfone; 4- [3- (4-trifluoromethoxyphenyl) -2-pyridinyl] -2-
4- [3- (3,4-Dichlorophenyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (3,4-dibromophenyl) -2-pyridinyl] -2 4- [3- (3,4-difluorophenyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (3,5-dichlorophenyl) -2-pyridinyl]- 2- [3- (3,5-dibromophenyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (3,5-difluorophenyl) -2-pyridinyl ] -2-Fluorophenylmethylsulfone; 4- [3- (3,4-dimethylphenyl) -2-pyridinyl] -2- 4- [3- (3,5-Dimethylphenyl) -2-pyridinyl] -2-fluorophenylmethylsulfone; 4- [3- (3-methyl-4-chlorophenyl) -2-pyridinyl] 2- [3- (4-methyl-3-chlorophenyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (3-methyl-4-fluorophenyl) -2-Pyridinyl] -2-
Fluorophenylmethyl sulfone; 4- [3- (4-methyl-3-fluorophenyl) -2-pyridinyl] -2-
4- [3- (3-Methyl-4-bromophenyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (4-methyl-3-bromophenyl) -2 -Pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (3-methyl-4-trifluoromethylphenyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (4-methyl -3-Trifluoromethylphenyl) -2-pyridinyl] -2-fluorophenylmethylsulfone; 4- [3- (3-Methyl-4-trifluoromethoxyphenyl) -2-pyridinyl] -2-fluorophenylmethylsulfone 4- [3- (4-methyl-3-trifluoromethoxyphenyl) -2-pyridinyl] -2-fluoro 4- [3- (3-cyano-4-methylphenyl) -2-pyridinyl] -2-fluorophenylmethylsulfone; 4- [3- (4-cyano-3-methylphenyl) -2- Pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (3-chloro-4-methoxyphenyl) -2-pyridinyl] -2-
Fluorophenyl methyl sulfone; 4- [3- (4-chloro-3-methoxyphenyl) -2-pyridinyl] -2-
4- [3- (2-methylpyridin-6-yl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (2-methylthiazol-4-yl) -2 -Pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (2-methylthiazol-2-yl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (2-methylpyridine- 3- [3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (2-methylpyridin-3-yl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (3-Pyridinyl) -2-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [3- (5-methylpyridin-3-yl) -2-pyri 4- [3- (2-methylpyridin-3-yl) -2-pyridinyl] -2-fluorophenylmethylsulfone; 4- [3-cyclohexyl-2-pyridinyl]- 4- [3-Cyclopentyl-2-pyridinyl] -2-fluorophenylmethylsulfone; 4- [4-phenyl-3-pyridinyl] -2-fluorophenylmethylsulfone; 4- [4- (3-chlorophenyl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (4-chlorophenyl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (3-bromo Phenyl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (4-bu Mophenyl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (3-fluorophenyl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (4-fluorophenyl) -4-Pyridinyl] -2-fluorophenylmethylsulfone; 4- [4- (3-methylphenyl) -3-pyridinyl] -2-fluorophenylmethylsulfone; 4- [4- (4-methylphenyl) -3 -Pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (3-cyanophenyl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (4-cyanophenyl) -3-pyridinyl ] -2-Fluorophenylmethylsulfone; 4- [4- (3-trifluoromethylphenyl) -3-pyridinyl 2- [4- (4-trifluoromethylphenyl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (3-trifluoromethoxyphenyl) -3- Pyridinyl] -2-
Fluorophenyl methyl sulfone; 4- [4- (4-trifluoromethoxyphenyl) -3-pyridinyl] -2-
4- [4- (3,4-Dichlorophenyl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (3,4-dibromophenyl) -3-pyridinyl] -2 4- [4- (3,4-difluorophenyl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (3,5-dichlorophenyl) -3-pyridinyl]- 2- [4- (3,5-dibromophenyl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (3,5-difluorophenyl) -3-pyridinyl ] -2-Fluorophenylmethylsulfone; 4- [4- (3,4-dimethylphenyl) -3-pyridinyl] -2- 4- [4- (3,5-Dimethylphenyl) -3-pyridinyl] -2-fluorophenylmethylsulfone; 4- [4- (3-methyl-4-chlorophenyl) -3-pyridinyl] 2- [4- (4-Methyl-3-chlorophenyl) -3-pyridinyl] -2-fluorophenylmethylsulfone; 4- [4- (3-methyl-4-fluorophenyl) -3-Pyridinyl] -2-
4- [4- (4-methyl-3-fluorophenyl) -3-pyridinyl] -2-
4- [4- (3-Methyl-4-bromophenyl) -3-pyridinyl] -2-fluorophenylmethylsulfone; 4- [4- (4-methyl-3-bromophenyl) -3 -Pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (3-methyl-4-trifluoromethylphenyl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (4-methyl -3-trifluoromethylphenyl) -3-pyridinyl] -2-fluorophenylmethylsulfone; 4- [4- (3-methyl-4-trifluoromethoxyphenyl) -3-pyridinyl] -2-fluorophenylmethylsulfone 4- [4- (4-methyl-3-trifluoromethoxyphenyl) -3-pyridinyl] -2-fluoro Nylmethyl sulfone; 4- [4- (3-cyano-4-methylphenyl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (4-cyano-3-methylphenyl) -3- Pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (3-chloro-4-methoxyphenyl) -3-pyridinyl] -2-
Fluorophenyl methyl sulfone; 4- [4- (4-chloro-3-methoxyphenyl) -3-pyridinyl] -2-
4- [4- (2-Methylpyridin-6-yl) -3-pyridinyl] -2-fluorophenylmethylsulfone; 4- [4- (2-methylthiazol-4-yl) -3 -Pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (4-methylthiazol-2-yl) -3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4- (2-methylpyridine- 4- [4- (4- (2-methylpyridin-3-yl) -3-pyridinyl] -2-fluorophenylmethylsulfone; 4- [4- (3-Pyridinyl) -3-pyridinyl) -3-pyridinyl] -2-
4- [4- (5-methylpyridin-3-yl) -3-pyridinyl] -2-fluorophenylmethylsulfone; 4- [4- (2-methylpyridin-3-yl) -3 -Pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4-cyclohexyl-3-pyridinyl] -2-fluorophenylmethyl sulfone; 4- [4-cyclopentyl-3-pyridinyl] -2-fluorophenylmethyl sulfone; -Chloro-3- (3-fluoro-4- (methylsulfonyl) phenyl) -2
-(Methyl-5-pyridinyl) pyridine; and pharmaceutically acceptable salts, tautomers and prodrugs thereof, but are not limited thereto.

[0110]   In one embodiment, the species is

[0111]

[Chemical 49]

And pharmaceutically acceptable salts, tautomers and prodrugs thereof. In another embodiment, the fluoro group is meta to the sulfonyl group.

[0113]   In another embodiment, the species is

[0114]

[Chemical 50]

And pharmaceutically acceptable salts, tautomers and prodrugs thereof. In another embodiment, the fluoro group is meta to the sulfonyl group.

Further Compounds In formula I, interesting compounds include 2-fluoro-4- [3-2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2 -Fluoro-4- [3- (3-chlorophenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4- Chlorophenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-bromophenyl) -2-oxo-2,3 -Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4-bromophenyl) -2-oxo-2,3-dihydro-1,3-thiazo 4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-fluorophenyl) -2-oxo-2,3
Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-fluorophenyl) -2-oxo-2,3-
Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methylphenyl)-[3-fluoro-4- (
Methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 2-fluoro-4- [3- (4-methylphenyl) -2-oxo-2,3-dihydro-1,3-thiazole -4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-cyanophenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2 -Fluoro-4- [3- (4-cyanophenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3 -Trifluoromethylphenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethylphenyl) ) -2-Oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethoxyphenyl) -2-oxo-2, 3-Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethoxyphenyl) -2-oxo-2,3-dihydro-1,3- Thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dichlorophenyl) -2-oxo-2,
3-Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dibromophenyl) -2-oxo-2,
3-Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-difluorophenyl) -2-oxo-2
, 3-Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dichlorophenyl) -2-oxo-2,
3-Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dibromophenyl) -2-oxo-2,
3-Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-difluorophenyl) -2-oxo-2
, 3-Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dimethylphenyl) -2-oxo-2,
3-Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dimethylphenyl) -2-oxo-2,
3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-chlorophenyl) -2-oxo-2,3-dihydro-1,3 2-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-chlorophenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl] Benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-fluorophenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2- Fluoro-4- [3- (4-methyl-3-fluorophenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-Fluoro- -[3- (3-Methyl-4-bromophenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4 -Methyl-3-bromophenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-tri] Fluoromethylphenyl)
2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-trifluoromethylphenyl)
2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-trifluoromethoxyphenyl) -2-oxo -2,3-Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-trifluoromethoxyphenyl) -2-oxo-2,3 -Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-cyano-4-methylphenyl) -2-oxo-2,3-dihydro-1,3 -Thiazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4-cyano-3-methylphenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl ] Benzenesulfonamide; 2-Fluoro-4- [3- (3-chloro-4-methoxyphenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2 -Fluoro-4- [3- (4-chloro-3-methoxyphenyl) -2-oxo-2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [ 3- (2-methylpyridin-6-yl) -2-oxo-
2,3-Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (2-methylthiazol-4-yl) -2-oxo-2,3-dihydro- 1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methylthiazol-2-yl) -2-oxo-2,3-dihydro-1,3-thiazol- 4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -2-oxo-
2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -2-oxo-
2,3-Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-pyridinyl) -2-oxo-2,3-dihydro-1,3-thiazole -4-yl] benzenesulfonamide; 2-fluoro-4- [3- (5-methylpyridin-3-yl) -2-oxo-
2,3-dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -2-oxo-
2,3-Dihydro-1,3-thiazol-4-yl] benzenesulfonamide; 3-Cyclohexyl-2-oxo-2,3-thiazol-4-yl] benzenesulfonamide; 3-Cyclopentyl-2-oxo- 2,3-thiazol-4-yl] benzenesulfonamide; 3-phenyl-4- [3-fluoro-4- (methylsulfonyl) phenyl]-
1,3-thiazol-2 (3H) -one; 3- (3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (4-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (3-bromophenyl) -4- [3 -Fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (4-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl]- 1,3-thiazol-2 (3H) -one; 3- (3-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one 3- (4-f) Orophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (3-methylphenyl) -4- [3-fluoro-4- (Methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (4-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazole -2 (3H) -one; 3- (3-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (4 -Cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (3-trifluoromethylphenyl) -4- [3- Fluoro-4- ( Methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (4-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3- Thiazol-2 (3H) -one; 3- (3-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3 -(4-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (3,4-dichlorophenyl) -4 -[3-Fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (3,4-dibromophenyl) -4- [3-fluoro-4- (methyl Rufonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (3,4-difluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazole -2 (3H) -one; 3- (3,5-dichlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- ( 3,5-Dibromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (3,5-difluorophenyl) -4- [3-Fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (3,4-dimethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) ) Phenyl -1,3-thiazol-2 (3H) -one; 3- (3,5-dimethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazole-2 (3H ) -One; 3- (3-methyl-4-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (4- Methyl-3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (3-methyl-4-fluorophenyl) -4 -[3-Fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (4-methyl-3-fluorophenyl) -4- [3-fluoro-4- (Methylsulfonyl) fe Nyl] -1,3-thiazol-2 (3H) -one; 3- (3-methyl-4-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazole -2 (3H) -one; 3- (4-methyl-3-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (3-Methyl-4-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (4-methyl -3-Trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (3-methyl-4-trifluoromethoxy Phenyl) -4 [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol -2 (3H) -
ON; 3- (4-methyl-3-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazole-2 (3H)-
3- (3-cyano-4-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (4-cyano -3-Methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3 (3-chloro-4-methoxyphenyl) -4- [3-Fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3 (4-chloro-3-methoxyphenyl) -4- [3-fluoro-4- (methyl Sulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (2-methylpyridin-6-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3 -Thiazole-2 (3 ) -One; 3- (2-methylthiazol-4-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (4 -Methylthiazol-2-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (2-methylpyridin-3-yl) -4- [3-Fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (2-methylpyridin-3-yl) -4- [3-fluoro- 4- (Methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (3-pyridyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3- Thiazol-2 (3H) -one; 3- (5-Methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3- (2-methylpyridin-3- Yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; 3-cyclohexyl-4- [3-fluoro-4- (methylsulfonyl) phenyl ] -1,3-Thiazol-2 (3H) -one; 3-Cyclopentyl-4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-thiazol-2 (3H) -one; and Another subclass consists of, but is not limited to, pharmaceutically acceptable salts, tautomers and prodrugs thereof.

Among the compounds of formula I, interesting compounds are: 2-fluoro-4- [3-2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro -4- [3- (3-chlorophenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-chlorophenyl) 2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-bromophenyl) -2-oxo-2,3-dihydro -1,3-Oxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4-bromophenyl) -2-oxo-2,3-dihydro-1,3-oxazole- - yl] benzenesulfonamide; 2-fluoro-4- [3- (3-fluorophenyl) -2-oxo-2,3
Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-fluorophenyl) -2-oxo-2,3-
Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-methylphenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4- 2-fluoro-4- [3- (4-methylphenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro- 4- [3- (3-cyanophenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-cyanophenyl) ) -2-Oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-trifluoromethylphenyl)- -Oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethylphenyl) -2-oxo-2,3-dihydro -1,3-Oxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-trifluoromethoxyphenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4 2-yl-4-benzenesulfonamide; 2-fluoro-4- [3- (4-trifluoromethoxyphenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2 -Fluoro-4- [3- (3,4-dichlorophenyl) -2-oxo-2,
3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dibromophenyl) -2-oxo-2,
3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-difluorophenyl) -2-oxo-2
, 3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dichlorophenyl) -2-oxo-2,
3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dibromophenyl) -2-oxo-2,
3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-difluorophenyl) -2-oxo-2
, 3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,4-dimethylphenyl) -2-oxo-2,
3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3,5-dimethylphenyl) -2-oxo-2,
3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-chlorophenyl) -2-oxo-2,3-dihydro-1,3 -Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-chlorophenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4-yl] Benzenesulfonamide; 2-Fluoro-4- [3- (3-methyl-4-fluorophenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2- Fluoro-4- [3- (4-methyl-3-fluorophenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2- Luoro-4- [3- (3-methyl-4-bromophenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3 -(4-Methyl-3-bromophenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl- 4-trifluoromethylphenyl)
2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methyl-3-trifluoromethylphenyl)
2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-methyl-4-trifluoromethoxyphenyl) -2-oxo -2,3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (4-methyl-3-trifluoromethoxyphenyl) -2-oxo-2,3 -Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-cyano-4-methylphenyl) -2-oxo-2,3-dihydro-1,3 -Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-cyano-3-methylphenyl) -2-oxo-2,3-dihydro-1,3-oxazole -4-yl] benzenesulfonamide; 2-fluoro-4- [3- (3-chloro-4-methoxyphenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzene 2-fluoro-4- [3- (4-chloro-3-methoxyphenyl) -2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-fluoro -4- [3- (2-methylpyridin-6-yl) -2-oxo-
2,3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (2-methylthiazol-4-yl) -2-oxo-2,3-dihydro- 1,3-Oxazol-4-yl] benzenesulfonamide; 2-fluoro-4- [3- (4-methylthiazol-2-yl) -2-oxo-2,3-dihydro-1,3-oxazol- 4-yl] benzenesulfonamide; 2-fluoro-4- [3- (2-methylpyridin-3-yl) -2-oxo-
2,3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (2-methylpyridin-3-yl) -2-oxo-
2,3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (3-pyridinyl) -2-oxo-2,3-dihydro-1,3-oxazole -4-yl] benzenesulfonamide; 2-fluoro-4- [3- (5-methylpyridin-2-yl) -2-oxo-
2,3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 2-Fluoro-4- [3- (2-methylpyridin-3-yl) -2-oxo-
2,3-Dihydro-1,3-oxazol-4-yl] benzenesulfonamide; 3-Cyclohexyl-2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzene-sulfonamide; 3 -Cyclopentyl-2-oxo-2,3-dihydro-1,3-oxazol-4-yl] benzene-sulfonamide; 3-phenyl-4- [3-fluoro-4- (methylsulfonyl) phenyl]-
1,3-Oxazol-2 (3H) -one; 3- (3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3-bromophenyl) -4- [3 -Fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (4-Bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl]- 1,3-Oxazol-2 (3H) -one; 3- (3-Fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one ; -(4-Fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3-methylphenyl) -4- [3 -Fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (4-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl]- 1,3-Oxazol-2 (3H) -one; 3- (3-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one 3- (4-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3-trifluoromethyl) -4 -[3- Fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (4-trifluoromethyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl]- 1,3-Oxazol-2 (3H) -one; 3- (3-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazole-2 (3H) -One; 3- (4-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3,4- Dichlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3,4-dibromophenyl) -4- [3 Fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3,4-difluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-Oxazol-2 (3H) -one; 3- (3,5-dichlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazole-2 (3H) -One; 3- (3,5-dibromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3,5- Difluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3,4-dimethylphenyl) -4- [3-fluoro 4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3,5-dimethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1 , 3-Oxazol-2 (3H) -one; 3- (3-methyl-4-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazole-2 (3H). -One; 3- (4-methyl-3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3-methyl -4-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (4-methyl-3-fluorophenyl) -4 − [3-Fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3-methyl-4-bromophenyl) -4- [3-fluoro-4- ( Methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (4-methyl-3-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1, 3-Oxazol-2 (3H) -one; 3- (3-methyl-4-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 ( 3H)-
ON; 3- (4-methyl-3-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazole-2 (3H)-
ON; 3- (3-methyl-4-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazole-2 (3H)
-One; 3- (4-methyl-3-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazole-2 (3H)
3- (3-cyano-4-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (4- Cyano-3-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3-chloro-4-methoxyphenyl)- 4- [3-Fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (4-chloro-3-methoxyphenyl) -4- [3-fluoro-4 -(Methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (2-methylpyridin-6-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl]- 1,3-Oki Zol-2 (3H) -one; 3- (2-Methylthiazol-4-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one 3- (4-methylthiazol-2-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (2-methylpyridine -3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (2-methylpyridin-3-yl) -4- [3-Fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (3-pyridinyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazo 3- (5-methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; 3-cyclohexyl-4- [ 3-fluoro-4- (methylsulfonyl) phenyl] -1,3-oxazol-2 (3H) -one; and 3-cyclopentyl-4- [3-fluoro-4- (methylsulfonyl) phenyl] -1, 3-oxazol-2 (3H) -one; and another subclass consisting of pharmaceutically acceptable salts, tautomers and prodrugs thereof, including but not limited to: Absent.

Among the compounds of formula I, interesting compounds include 5-phenyl-4- [3-fluoro-4- (methylsulfonyl) phenyl]-
2- (difluoromethyl) -1H-imidazole; 5- (3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (4 -Chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3-bromophenyl) -4- [3-fluoro-4- ( Methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (4-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H -Imidazole; 5- (3-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (dif 5- (4-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3-methylphenyl) ) -4- [3-Fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (4-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) ) Phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole 5- (4-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl 1-H-imidazole; 5- (3-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (4-trifluoro Methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3-trifluoromethoxyphenyl) -4- [3-fluoro-4 -(Methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (4-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoro Methyl) -1H-imidazole; 5- (3,4-dichlorophenyl) -4- [3-fluoro-4- (methyls Rufonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3,4-dibromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl)- 1-H-imidazole; 5- (3,4-difluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3,5-dichlorophenyl) ) -4- [3-Fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3,5-dibromophenyl) -4- [3-fluoro-4- ( Methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3,5-difluorophenyl) -4- [3-phenyl Oro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3,4-dimethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 -(Difluoromethyl) -1H-imidazole; 5- (3,5-dimethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3-Methyl-4-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (4-methyl-3-chlorophenyl) -4 -[3-Fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3-methyl- -Fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (4-methyl-3-fluorophenyl) -4- [3- Fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3-methyl-4-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (4-methyl-3-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H- Imidazole; 5- (3-methyl-4-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (Difluoromethyl) -1H-imidazole; 5- (4-methyl-3-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole 5- (3-methyl-4-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-
Imidazole; 5- (4-methyl-3-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-
5- (3-cyano-4-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (4-cyano-3) -Methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3-chloro-4-methoxyphenyl) -4- [3- Fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (4-chloro-3-methoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] 2- (difluoromethyl) -1H-imidazole; 5- (2-methylpyridin-6-yl) -4- [3-fluoro-4- (methylsulfo Phenyl) -2- (difluoromethyl) -1H-imidazole; 5- (2-methylthiazol-4-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl ) -1H-imidazole; 5- (4-methylthiazol-2-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (2 -Methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (2-methylpyridin-3-yl) -4 -[3-Fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (3-pyridinyl) -4- [3-phenyl Oro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (5-methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H- Imidazole; 5-Cyclohexyl-4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (difluoromethyl) -1H-imidazole; 5-Cyclopentyl-4- [3-fluoro-4- (methylsulfonyl) Phenyl] -2- (difluoromethyl) -1H-imidazole; 5-phenyl-4- [3-fluoro-4- (methylsulfur) Phenyl) phenyl]-
2- (trifluoromethyl) -1H-imidazole; 5- (3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (4-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3-bromophenyl) -4- [3-fluoro- 4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (4-bromophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (tri Fluoromethyl) -1H-imidazole; 5- (3-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl]- 5- (trifluoromethyl) -1H-imidazole; 5- (4-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3-Methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (4-methylphenyl) -4- [3-fluoro -4- (Methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- ( Trifluoromethyl) -1H-imidazole; 5- (4-cyanophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2 (Trifluoromethyl) -1H-imidazole; 5- (3-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; -(4-Trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3-trifluoromethoxyphenyl) -4 -[3-Fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (4-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) ) Phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3,4-dichlorophenyl) -4- [3-Fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3,4-dibromophenyl) -4- [3-fluoro-4- (methylsulfonyl) Phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3,4-difluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl)- 1-H-imidazole; 5- (3,5-dichlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3,5-dibromo Phenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3 5-difluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3,4-dimethylphenyl) -4- [3- Fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3,5-dimethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl]- 2- (trifluoromethyl) -1H-imidazole; 5- (3-methyl-4-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H- Imidazole; 5- (4-methyl-3-chlorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoro Methyl) -1H-imidazole; 5- (3-Methyl-4-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (4-Methyl-3-fluorophenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3-methyl-4-bromophenyl ) -4- [3-Fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (4-methyl-3-bromophenyl) -4- [3-fluoro- 4- (Methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3-methyl-4-trifluoromethylphenyl)- - [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl)-1H-
Imidazole; 5- (4-methyl-3-trifluoromethylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-
Imidazole; 5- (3-methyl-4-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H
-Imidazole; 5- (4-methyl-3-trifluoromethoxyphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H
-Imidazole; 5- (3-cyano-4-methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (4-cyano -3-Methylphenyl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3-chloro-4-methoxyphenyl) -4- [3-Fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (4-chloro-3-methoxyphenyl) -4- [3-fluoro-4- (methyl Sulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (2-methylpyridin-6-yl) -4- [3-fluoro-4- (me 2- (trifluoromethyl) -1H-imidazole; 5- (2-methylthiazol-4-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- ( Trifluoromethyl) -1H-imidazole; 5- (4-methylthiazol-2-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (2-methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (2-methylpyridin-3) -Yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (3-pyridi ) -4- [3-Fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (5-methylpyridin-3-yl) -4- [3-fluoro -4- (Methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5- (2-Methylpyridin-3-yl) -4- [3-fluoro-4- (methylsulfonyl) phenyl] 2- (Trifluoromethyl) -1H-imidazole; 5-Cyclohexyl-4- [3-fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; 5-Cyclopentyl-4 -[3-Fluoro-4- (methylsulfonyl) phenyl] -2- (trifluoromethyl) -1H-imidazole; and their pharmaceuticals Another subclass consists of, but is not limited to, pharmaceutically acceptable salts, tautomers and prodrugs.

Definitions The term "hydride" represents one hydrogen atom (H). The hydride group forms a hydroxyl group when attached to, for example, one oxygen atom, and the two hydride groups form a methylene (—CH ₂ —) group when attached to a carbon atom.

The term “alkyl”, when used alone or in other terms, such as “haloalkyl”, “alkylsulfonyl” and “alkoxyalkyl”,
It has 1 to about 20 carbon atoms, or, preferably, 1 to about 12
Included are straight chain or branched groups having 3 carbon atoms. More preferred alkyl groups are "lower alkyl" groups having 1 to about 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, iso-amyl, hexyl and the like. Even more preferred is lower alkyl having 1 to 3 carbon atoms.

The term “alkenyl”, when used alone or in other terms, such as “arylalkenyl”, means that it has from 2 to about 20 carbon atoms, preferably 2 carbon atoms.
To linear or branched groups having at least one carbon-carbon double bond having from about 12 carbon atoms. More preferred alkenyl groups are "lower alkenyl" groups having 2 to about 6 carbon atoms. Examples of alkenyl groups include:
Mention is made of ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.

The terms "alkenyl" and "lower alkenyl" refer to "cis" and "
Includes groups having the "trans" orientation, or alternatively, the "E" and "Z" orientations. The term "alkynyl" has 2 to about 20 carbon atoms, preferably 2 to about 12 carbon atoms. It represents a straight-chain or branched radical, more preferred alkynyl radicals are "lower alkynyl" radicals having two to about ten carbon atoms.
Most preferred are lower alkynyl groups having from about 6 carbon atoms. Examples of such groups include propargyl, butynyl and the like.

The term “cycloalkyl” includes saturated carbocycles having 3 to about 12 carbon atoms. Further preferred "cycloalkyl groups" are "lower cycloalkyl" groups having from 3 to about 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term “cycloalkenyl” embraces partially saturated carbocyclic groups having 3-12 carbon atoms. A cycloalkenyl group which is a partially saturated carbocyclic group containing two double bonds (which may be conjugated or non-conjugated) is
It can also be referred to as "cycloalkyldienyl". More preferred cycloalkenyl groups are "lower cycloalkenyl" groups having from 4 to about 8 carbon atoms.
Examples of such groups include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The terms “halo” and “halogen” mean halogen, for example fluorine, chlorine, bromine or iodine atoms. The term "haloalkyl" embraces radicals in which any one or more of the alkyl carbon atoms is substituted with halo as defined above. As one example, a monohaloalkyl group can have either iodo, bromo, chloro or fluoro within the group. The dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups. "Lower haloalkyl" embraces radicals having 1-6 carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl. And dichloropropyl. "Perfluoroalkyl" means an alkyl group in which all hydrogen atoms have been replaced with fluorine atoms. Examples include trifluoromethyl and pentafluoroethyl.

The terms “hydroxyalkyl” and “hydroxylalkyl” refer to straight or branched chain having from 1 to about 10 carbon atoms, any one of which may be substituted with one or more hydroxyl groups. Including an alkyl group. More preferred hydroxyalkyl groups are "lower hydroxylalkyl" groups having 1 to 6 carbon atoms and one or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl having 1 to 3 carbon atoms.

The term “cyanoalkyl” embraces straight-chain or branched alkyl groups having 1 to about 10 carbon atoms, any one of which may be substituted with one or more cyano groups. . More preferred cyanoalkyl groups are "lower cyanoalkyl" groups having 1 to 6 carbon atoms and one cyano group. Even more preferred are lower cyanoalkyl groups having 1 to 3 carbon atoms. An example of such a group is cyanomethyl.

The term “aryl”, alone or in combination, refers to a carbocyclic aromatic containing one or two rings in which such rings may be side-chained or fused to each other. Means a tribe system. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. A more preferred aryl is phenyl. The “aryl” group may have 1 to 3 substituents, such as lower alkyl, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino.

The term “heterocyclyl” or “heterocyclo” embraces radicals of the 3-10 membered saturated, partially saturated and unsaturated heteroatom-containing ring form, in which the heteroatoms are nitrogen, sulfur and oxygen. You can choose from. A more preferred heterocyclyl group is a 5-8 membered heterocyclyl. Examples of the saturated heterocyclic group include a saturated 3-6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms [eg,
Pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl]; saturated 3-6 membered heteromonocyclic ring containing 1-2 oxygen atoms and 1-3 nitrogen atoms [eg morpholino]; 1-2 sulfur atoms And saturated 3-6 membered heteromonocyclic ring groups containing 1 to 3 nitrogen atoms [eg thiazolidinyl]. Examples of partially saturated heterocyclyl groups include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Unsaturated heteromonocyclic rings are also referred to as "heteroaryl", examples of which include 5-6 membered heteromonocyclic ring groups containing 1 to 4 nitrogen atoms, for example pyrrolinyl, imidazolyl. , Pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [for example, 4H-1,2,4-triazolyl, 1
H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; a saturated fused heterocyclic ring group containing 1 to 5 nitrogen atoms, for example, indolyl, indolizinyl, benzimidazolyl, quinolyl, Isoquinolyl, indazolyl, benztriazolyl, tetrazolopyridazinyl [for example, tetrazolo [1,5-b] pyridazinyl]; unsaturated heteromonocyclic ring group containing one oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc .; unsaturated 5-6 membered heteromonocyclic ring containing one sulfur atom, for example, 2-thienyl, 3-thienyl, etc .; 1-2 oxygen atoms and 1- Unsaturated 5- to 6-membered heterocyclic ring groups containing 3 nitrogen atoms, eg isoxazolyl, oxadiazolyl [eg 1,2,4-oxadiazolyl, 1,3,4- Kisajiazoriru, 1,2,5-oxadiazolyl]; 1
Unsaturated condensed heterocyclic ring group containing 3 oxygen atoms and 1 to 3 nitrogen atoms [eg, benzoxazolyl, benzoxadiazolyl]; 1 to 2 sulfur atoms and 1 to 3 A nitrogen atom of, for example, thiazolyl, thiadiazolyl [for example,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]; unsaturated fused heterocyclic ring containing 1-2 sulfur atoms and 1-3 nitrogen atoms And groups such as benzothiazolyl and benzothiadiazolyl. The term also includes groups in which a heterocyclic group is fused with an aryl group. Examples of such fused bicyclic ring groups include benzofuran, benzothiophene, and the like. Said "heterocyclyl" group may have 1 to 3 substituents, such as lower alkyl, hydroxy, oxo, amino and lower alkylamino.

The heterocyclic ring group may include a 3-10 membered fused or unfused group. Preferred examples of heteroaryl groups include benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazole, indolyl, dihydroindolyl, chromanyl, benzopyranyl, thiochromanyl, benzothiopyran, benzodioxanyl, pyridyl, thienyl, thiazolyl, furyl and Examples include pyrazinyl. More preferred heteroaryl groups are 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from sulfur, nitrogen and oxygen, and are thienyl, furanyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, It is selected from pyridyl, piperidinyl and pyrazinyl.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferred aralkyl groups are "lower aralkyl" groups having an aryl group attached to an alkyl group having 1 to 6 carbon atoms. Even more preferred are lower aralkyl groups having phenyl attached to the alkyl moiety having 1 to 3 carbon atoms. Examples of such groups include benzyl, diphenylmethyl and phenylethyl. The aryl of said aralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The term "arylalkenyl" embraces aryl-substituted alkenyl groups.
Preferred arylalkenyl groups are "lower arylalkenyl" having an aryl group attached to an alkenyl group having 2 to 6 carbon atoms. Examples of such groups include phenylethenyl. The aryl of said arylalkenyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The aryl of said aralkyl and arylalkenyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.

Benzyl and phenylmethyl are interchangeable terms. The term "heterocyclylalkyl" embraces heterocyclic ring-substituted alkyl radicals. More preferred heterocyclylalkyl groups are "5- or 6-membered heteroarylalkyl" groups having an alkyl moiety having 1 to 6 carbon atoms and a 5- or 6-membered heteroaryl group. Even more preferred are lower arylalkyl groups having an alkyl moiety with 1 to 3 carbon atoms. Examples include groups such as pyridylmethyl and thienylmethyl.

The terms “alkoxy” and “alkyloxy” include linear or branched oxy-containing groups each having an alkyl moiety having 1 to about 10 carbon atoms. More preferred alkoxy groups are "lower alkoxy" groups having 1 to 6 carbon atoms. Examples of such groups include methoxy, ethoxy, propoxy, butoxy and t-butoxy. Even more preferred are lower alkoxy groups having 1 to 3 carbon atoms. An "alkoxy" group may be further substituted with one or more halo atoms such as fluoro, chloro or bromo to give a "haloalkoxy". Even more preferred are lower haloalkoxy groups having 1 to 3 carbon atoms. Examples of such groups include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term "alkoxyalkyl" embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical,
That is, monoalkoxyalkyl and dialkoxyalkyl groups are formed.

The term “aryloxy” embraces aralkyl radicals attached through an oxygen atom to other radicals. The term "aryloxy" embraces aryloxy radicals as defined above linked via an oxygen atom to an alkyl radical. The term "heterocyclyloxy" embraces heterocyclyl radicals attached through an oxygen atom to another radical.

The term “alkylsulfonyl” embraces radicals containing a straight-chain or branched alkyl radical having 1 to 10 carbon atoms attached to a divalent —S (═O) — atom. More preferred is a lower alkylsulfinyl group having 1 to 3 carbon atoms.

The term “sulfonyl” is used alone or in combination with other terms to define “
"Alkylsulfonyl" and "arylsulfonyl" are each a divalent group-
Represents SO ₂ −. "Alkylsulfonyl" embraces alkyl radicals attached to a sulfonyl radical, where alkyl is as defined above. More preferred alkylsulfonyl groups are "lower alkylsulfonyl" groups having 1 to 6 carbon atoms. Even more preferred are lower alkylsulfonyl groups having 1 to 3 carbon atoms. Examples of such lower alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl and propylsulfonyl. “Arylsulfonyl” includes a group bound to a sulfonyl group, where aryl is as defined above. A preferred arylsulfonyl group is phenylsulfonyl.

The terms “sulfamyl”, “aminosulfonyl” and “sulfonamidyl” are used alone or in combination with other terms to “N-alkylaminosulfonyl” and “N-arylaminosulfonyl”, “ N, N-dialkylaminosulfonyl "and" N-alkyl--N- allyl aminosulfonyl "denotes a sulfonyl radical substituted with an amine group to form a sulfonamide (-SO ₂ NH _2). The term "alkylaminosulfonyl" includes "N-alkylaminosulfonyl" and "N, N-dialkylaminosulfonyl", where the sulfamyl group is substituted with one alkyl or two alkyl groups, respectively. ing. More preferred alkylaminosulfonyl groups are "lower alkylaminosulfonyl" groups having 1 to 6 carbon atoms. Even more preferred are lower alkylaminosulfonyl groups having 1 to 3 carbon atoms. Examples of such lower alkylaminosulfonyl groups include N-methylaminosulfonyl, N-ethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl. The terms "N-arylaminosulfonyl" and "N-alkyl-N-arylaminosulfonyl" represent a sulfamyl group substituted with one alkyl group or one alkyl and one aryl group, respectively. More desirable N
An -alkyl-N-arylaminosulfonyl group is a "lower N-aryl-N-arylsulfonyl" group having an alkyl group having 1-6 carbon atoms.
Even more preferred are N-alkyl-N-arylsulfonyl groups having 1 to 3 carbon atoms. Examples of such lower N-aryl-N-arylsulfonyl groups include N-methyl-N-phenylaminoalkyl and N-ethyl-N-phenylaminosulfonyl. Examples of such N-aryl-aminosulfonyl group include N-phenylaminosulfonyl.

The term “alkylthio” embraces radicals containing a straight-chain or branched alkyl radical having 1 to 10 carbon atoms attached to a divalent sulfur atom. 1 to
Even more preferred are lower alkylthio groups having 3 carbon atoms. Examples of "alkylthio" is methylthio (CH ₃ -S). The term "alkylthioalkyl" embraces radicals containing an alkylthio radical attached to the alkyl radical of 1 to about 10 carbon atoms through a divalent sulfur atom. Further preferred alkylthioalkyl groups are "lower alkylthioalkyl" groups having an alkyl group with 1 to 6 carbon atoms. An example of such a lower alkylthioalkyl group is methylthiomethyl.

The term “arylthio” embraces aryl radicals having 6-10 carbon atoms attached to a divalent sulfur atom. An example of "arylthio" is phenylthio. The term "aralkylthio" embraces aralkyl radicals as defined above attached to a divalent sulfur atom. Phenyl -C ₁ -C ₃ - alkylthio group is more preferable. An example of "aralkylthio" is benzylthio. The term "arylthioalkyl" embraces arylthio groups as defined above attached to an alkyl group via a sulfur atom.

The term “carboxy” or “carboxyl” is used alone or in combination with other terms, for example “carboxyalkyl” refers to —CO ₂ H.
The term "carboxyalkyl" embraces radicals having a carbonyl group as defined above attached to an alkyl radical.

The term “carbonyl” is used alone or in combination with other terms, for example “alkylcarbonyl” represents — (C═O) —. The term "alkylcarbonyl" embraces radicals having a carbonyl radical substituted with an alkyl radical. More preferred alkylcarbonyl groups are "lower alkylcarbonyl" having 1 to 6 carbon atoms. Even more preferred are lower alkylcarbonyl groups having 1 to 3 carbon atoms. The term "alkylcarbonyl" includes an alkyl, hydroxyalkyl group, as defined herein, attached to a carbonyl group. Examples of such groups include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl.

The term “arylcarbonyl” embraces radicals having a carbonyl radical substituted with an aryl radical. A more preferred arylcarbonyl group is phenylcarbonyl. The term "aralkylcarbonyl" embraces radicals having a carbonyl radical substituted with an arylalkyl radical. A more preferred group is phenyl-C ₁ -C ₃ -alkylcarbonyl, including benzylcarbonyl.

The term “alkoxycarbonyl” means a group containing an alkoxy group, as defined above, attached to a carbonyl group via an oxygen atom. Preferably, "lower alkoxycarbonyl" groups include alkoxy groups having 1-6 carbon atoms. Examples of such "lower alkoxycarbonyl" ester groups include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. Even more preferred are lower alkoxycarbonyl groups having an alkoxy moiety having 1 to 3 carbon atoms. The term "alkoxycarbonylalkyl" embraces alkyl radicals substituted with an alkoxycarbonyl as defined above. More preferred are "lower alkoxycarbonylalkyl" groups having an alkyl moiety having 1 to 6 carbons. Examples of such lower alkoxycarbonylalkyl groups include substituted or unsubstituted methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl and ethoxycarbonylethyl.

The term “aminocarbonyl”, when used with itself or other terms, includes, for example, “aminocarbonylalkyl”, “N-alkylaminocarbonyl”, “N-arylaminocarbonyl”, “N, N”. -Dialkylaminocarbonyl ", N-alkyl-N-arylaminocarbonyl", "N-alkyl-N-
“Hydroxyaminocarbonyl” and “N-alkyl-N-hydroxyaminocarbonyl” represent an amide group represented by the formula —C (═O) NH _2. “N-alkylaminocarbonyl” and “N, N-dialkyl. The term "aminocarbonyl" refers to an aminocarbonyl group substituted by one alkyl group and two alkyl groups, respectively. "Lower alkylaminocarbonyl" having a lower alkyl group as defined above attached to an aminocarbonyl group is further Preferred "N-arylaminocarbonyl" and "N-alkyl-N-arylaminocarbonyl"
The terms respectively represent an aminocarbonyl group substituted with one aryl group or one alkyl group and one aryl group.

The term "aminoalkyl" embraces alkyl radicals substituted with amino radicals. The term "alkylaminoalkyl" embraces aminoalkyl radicals having the nitrogen substituted with an alkyl radical. Even more preferred are lower alkylaminoalkyl radicals having one to three carbon atoms.

The terms “N-alkylamino” and “N, N-dialkylamino” refer to
Each represents an amino group substituted with one alkyl group and two alkyl groups. More preferred alkylamino groups are "lower alkylamino" groups having one or two alkyl groups having 1-6 carbon atoms attached to the nitrogen. Even more preferred are lower alkylamino groups having 1 to 3 carbon atoms. Suitable "alkylamino" may be mono or dialkylamino, such as N-methylamino, N, N-dimethylamino, N, N-diethylamino and the like. The term "arylamino" refers to an amino group substituted with one or two aryls, eg N-phenylamino. An "arylamino" group may be further substituted on the aryl ring portion of the group. The term "aralkylamino" refers to an amino group substituted with one or two aralkyl groups.
Further preferred is a phenyl-C ₁ -C ₃ -arylamino group, eg N-benzylamino. An "aralkylamino" group may be further substituted on the aryl ring portion of the group. The terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino" refer to an amino group, respectively, one aralkyl and one alkyl group, or one aryl and one aryl group. It represents an amino group which may be substituted with an alkyl group.

The term “aminocarbonyl” refers to an amide group of the formula —C (═O) NH ₂ . The term “alkylaminocarbonyl” means 1 on the amino nitrogen atom.
Represents an aminocarbonyl group substituted with one or two alkyl groups. "N-
"Alkylaminocarbonyl" and "N, N-dialkylaminocarbonyl" groups are preferred, "lower N-alkylaminocarbonyl" and "lower N, N-dialkylaminocarbonyl" having a lower alkyl moiety as defined above are more preferred. The term "alkylaminoalkyl" embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical. The term "arylaminoalkyl" embodies one or more aryl radicals attached to an aminoalkyl radical. And groups having

Additional terms used to describe the substituents of the compounds of Formulas I-VII and not otherwise defined herein are defined as set forth in the definitions above.

The terms “treatment” and “treating” refer to medical treatment with the purpose of improving the condition of a subject directly or indirectly, or delaying the progression of the condition or disease of a subject, including humans. Refers to any process, action, application, treatment, etc. of receiving an aid.

The term “prevention” or “prophylactic treatment” may prevent the onset of any clinically manifest inflammation or inflammation-related disease, or preclinically manifest in an individual with inflammation or inflammation-related disease. Including preventing the initiation of stages.

The term “therapeutically effective” refers to the amount of each agonist that will achieve the goal of amelioration in disease severity and frequency of occurrence, but will avoid side effects typically associated with another treatment. Is intended to be qualitative.

The term “prodrug” refers to compounds that are drug precursors that are converted in vivo to the active species by some process, eg metabolic conversion, following administration to a subject and subsequent absorption. Other products from the conversion process are easily discarded by the body. Further preferred prodrugs are generally produced from conversion processes that are considered safe. By way of example, and not of limitation, U.S.P. S. Patent 5,932,598 describes prodrug forms of compounds that are substituted sulfonamide compounds that selectively inhibit cyclooxygenase-2. For example, the prodrug may be an active compound, eg, an acylated form of an acylated sulfonamide.

The term “co-therapy” (or “combination therapy”) defines a use of a cyclooxygenase-2 inhibitor and another pharmaceutical formulation, a formulation that will result in the beneficial effect of the drug combination. Is intended to include sequential administration of each agonist, as well as co-administration of these agonists at substantially the same time, eg, a single capsule having a fixed ratio of these active agents. It is intended to be administered in or in multiple separate capsules of each agonist.

[0154] stereoisomers, tautomers, as a family of compounds represented by the protected acid and salts Formula I-VII, also including enantiomers, diastereomers, racemic mixtures and other mixtures thereof Stereoisomers may be included, but are not limited to.

The family of compounds of formulas I-VII also includes tautomers of these compounds. The family of compounds of formulas I-VII also includes their protected acids, such as esters, hydroxyamino derivatives, amides and sulfonamides. Thus, for example, primary and secondary amines can be reacted with carboxylic acid substituted forms of Formulas I-VII to form amides that may be useful as prodrugs. Preferred amines are heterocyclic amines, including optionally substituted aminothiazole, optionally substituted amino-isoxazole and optionally substituted aminopyridine; aniline derivatives; sulfonamides; aminocarboxylic acids and the like. Is. Esters, hydroxyamino derivatives and sulfonamides can be prepared from acids by methods known to those skilled in the art. The family of compounds of formulas I-VII also includes pharmaceutically acceptable salts thereof. The term "pharmaceutically acceptable salt" includes salts that are commonly used to form alkali metal salts or free acid or free base addition salts. The nature of the salt is not critical so long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds of formulas I-VII are:
It can be produced from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic acids; and organic sulfonic acids, examples of which are formic acid, acetic acid, propionic acid. , Succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anitranilic acid, mesylic acid, salicylic acid , 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, emonic acid (permoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfanilic acid, Cyclohexylaminosulfonic acid, stearyl acid, alginic acid, N-hydride Carboxymethyl acid, salicylic acid, a galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of the compounds of formulas I-VII include metal salts, for example salts of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc; or Salts of organic salts, including primary, secondary and tertiary amines; cyclic amines such as caffeine,
Substituted amines include arginine, diethylamine, N-ethylpiperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts include, for example, a suitable acid or base of formula IV
It can be prepared by a conventional means from the corresponding compound of the present invention by reacting with the compound represented by II.

Pharmaceutical Compositions One or more of the active compounds of Formulas I-VII and one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively Also included in the invention is a class of pharmaceutical compositions that includes a "carrier" material herein) and optionally other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the intended treatment. The active compounds and compositions can be administered, for example, orally, pulmonary artery, mucosa, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition preferably consists of dosage units containing individual amounts of the active ingredients. Examples of such dosage units are tablets or capsules. The active ingredient can also be administered by injection as a composition in which, for example, sarin, dextrose or water can be used as a suitable carrier.

The amount of therapeutically active compound administered and the dosing regimen for treating a disease state with the compounds and / or compositions of the present invention may vary according to age, weight, sex and medical condition of the patient, of the disease. It depends on a number of factors, including the severity, route and frequency of administration, the particular compound used, and thus can vary widely. The pharmaceutical composition has an active ingredient in the range of about 0.1 to 2000 mg, preferably about 0.5 to 500 mg.
It should be included in the range of 0 mg, most preferably in the range of about 1-100 mg. 0
． Daily dose of 01-100 mg / kg body weight, preferably about 0.5 to about 20 mg /
A daily dose of kg body weight, most preferably about 0.1-10 mg / kg body weight, will be suitable. The daily dose can be administered by administration 1 to 4 times per day.

In psoriasis and other skin conditions, it is preferred to apply the topical formulations of the present invention to the infected area 2 to 4 times per day. For inflammation of the eye and other external tissues, for example mouth and skin, the formulations may combine total active ingredients, for example 0.075 to 30% w / w, preferably 0.2.
It is preferably applied as a topical ointment or cream containing in an amount of -20% w / w, most preferably 0.4-15% w / w, or as a suppository. When formulated in an ointment, the active ingredient can be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base is, for example, at least 30% w / w polyhydric alcohol, such as propylene glycol, butane-1.
, 3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. Topical formulations desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other infected areas. Examples of such skin penetrants include dimethyl sulfoxide and related analogs. The compounds of the present invention can also be administered by a transdermal device. Preferably topical administration will be achieved using reservoirs and porous membrane type patches or solid matrix species. In each case, the active ingredient is continuously delivered from the reservoir or microcapsules through the membrane to the active agent, a permeable adhesive, which is contacted with the skin or mucous membranes of the recipient. When the active agent is delivered through the skin, a controlled and predetermined flow rate of the active agent is administered to the recipient. In the case of microcapsules, the encapsulant can function as a membrane.

The oily phase of the emulsions of the present invention can be composed of known ingredients in a known manner. Although the phase simply comprises an emulsifier, it comprises a mixture of at least one emulsifier with a fat or oil or with a fat and oil. Preferably, a hydrophilic emulsifier is included with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both oils and fats. The emulsifier, with or without stabilizers, forms the so-called emulsified wax, which together with the oil and fat forms the so-called emulsified ointment base which forms the oily dispersed phase of the cream formulation. Suitable emulsifiers and emulsion stabilizers for use in the formulations of the present invention include, among others, Tween 60, S
pan 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

The selection of suitable oils or fats for the formulation achieves the desired cosmetic properties because the solubility of the active compound in most oils, which tends to be used in pharmaceutical emulsion formulations, is very low. Depends on what you do. Thus, the cream should preferably be non-greasy, non-staining and washable with suitable consistency to avoid leakage from tubes or other containers. Linear or branched chain mono-
Or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl palmitate, butyl stearate, 2-ethylhexyl palmitate. Tates or blends of esters with branched chains can be used. These can be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin; or other mineral oils can be used.

Formulations suitable for topical administration to the eye include the active ingredient in a suitable carrier,
Particular mention is made of eye drops dissolved or suspended in an aqueous solvent for the active ingredient. The anti-inflammatory active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, especially about 1.5% w / w. .

For therapeutic purposes, the active compounds of this combined invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. When administered orally, the compounds include lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, acacia, alginic acid. It can be mixed with sodium, polyvinylpyrrolidone, and / or polyvinyl alcohol and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of hydroxypropylmethylcellulose of the active compound. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned above used in the formulation for oral administration. The compound is water, polyethylene glycol,
Propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,
It can be dissolved in benzyl alcohol, sodium chloride, and / or various buffers. Modes of administration and other adjuvants are well and widely known in the pharmaceutical art.

For pulmonary administration, the pharmaceutical composition can be administered in the form of an aerosol; or in the form of an inhalant, including dry powder aerosol.

General Synthetic Methods The compounds of the present invention can be synthesized according to the methods shown below. The substituents of the compounds shown in the methods below generally have the same definitions as the substituents at the corresponding positions of the compounds of formula I-VII, except where otherwise indicated. For example, unless otherwise indicated, the following R ¹ as used in the method, R ² and R ³ corresponds to R ^1, R ² and R ³ as defined above; corresponding to substituent R ^3A and R ^3B are independently selected from R ³ as previously defined; and R ^S corresponding to the functional group is hydrogen and R ¹ , cyclohexyl, pyrimidinyl and phenyl moieties previously described. Selected from the group consisting of any defined substituents. Unless otherwise indicated, X as used in the methods below corresponds to halogen.

[0166]

[Chemical 51]

3-Fluoro-4-methylsulfonylphenyl (1) and 3-fluoro-4
-Aminosulfonylphenyl (2) is a specific regiochemically substituted aromatic ring present in the cyclooxygenase-2 inhibiting diaryl-heterocycle disclosed in this application. The 3-fluoro-4-methylsulfonylphenyl (1) and 3-fluoro-4-aminosulfonylphenyl (2) ring functionalities described are as follows for various diaryl substituted heterocycles disclosed in this application. Can be prepared using the synthetic methodology outlined in.

[0168]

[Chemical 52]

Methylthio (3) groups are treated with methyl sulfone (1 ) Can be converted to.

[0170]

[Chemical 53]

Sulfonamide (2) can be obtained from sulfone (1) by treatment with an alkyl base such as butyllithium, methyllithium, etc. in an ethereal solvent such as tetrahydrofuran at about -78 ° C. it can. In the second step,
A trialkylboron such as triethylboron or tributylboron is added to form the intermediate borate (4), warmed to room temperature and then stirred for 16 hours or a suitable time. The solution is cooled to room temperature and water, sodium acetate and hydroxylamine-O-sulfonic acid are added to give the sulfonamide (2) [Huan
g; Tetrahedron Letters, 35, 7201-7204 (1
994)].

[0172]

[Chemical 54]

In Scheme II, sulfonamide (2) can be obtained by treating sulfone (1) with an alkyl base such as butyllithium. Addition of trimethylsilyl-methyl chloride gives trimethylsilylethyl sulfone (5). Following desilylation by addition of a reagent such as tetra-n-butylammonium fluoride to a solution of sulfone (5), in situ ethylene extrusion gives sulfinic acid (6) [Vhu; Steroid, 67, 543-545
(1997)]. Sulfinic acid (6) can be converted to sulfonamide (2) by addition of sodium acetate and hydroxylamine-O-sulfonic acid.

[0174]

[Chemical 55]

In Scheme III, the sulfonamide (2) is converted from the methylthio group (3) to
1 equivalent of m-chloroperbenzoic acid, monoperoxyphthalic acid, peroxide or OX
It can be prepared by conversion of the methylthio moiety to the sulfoxide by the careful addition of an oxidizing agent such as ONE®. The Pummer transition, which is carried out by mixing the obtained sulfoxide in anhydride and subsequent heating, is carried out by the thioacetal (7
)give. Oxidation to the sulfone as previously described, treatment with a hydroxide or alkoxide gives sulfinic acid (6) [Vleeshauer.
Syn. Lett. , 4,375-377 (1997)], in a hydroalcoholic solvent such as methanol-water or ethanol-water by the addition of a suitable base such as sodium acetate and hydroxylamine-O-sulfonic acid (2 ) Can be converted to.

[0176]

[Chemical 56]

Alternatively, Scheme IV illustrates a further alternative method for the preparation of sulfonamide (2) starting from the corresponding methylthio moiety. First, methylthio (3)
Conversion of the moiety to methyl sulfoxide is accomplished by the careful addition of one equivalent of m-chloroperbenzoic acid, monoperoxyphthalic acid, peroxide or an oxidizing agent such as OXONE®. Methyl sulfoxide is then mixed with trifluoroacetic acid in various inert solvents such as dichloromethane and post-treated with water to give the sulfide (8). Treatment of the sulfide (8) with chlorine gives the sulfonyl chloride (9). Finally, addition of ammonia to the sulfonyl chloride (9) gives the desired sulfonamide (2) [Kharash, J. et al. Am. Chem
． Soc. , 73, 3240 (1951)].

[0178]

[Chemical 57]

3-Fluoro-4-methylthiophenyl-substituted-phenyl-ethanone (10)
And (11) are intermediates used in the preparation of many of the diaryl-heterocycles disclosed in this application. The following discussion shows representative methods for making these intermediates.

[0180]

[Chemical 58]

Scheme V outlines the preparation of deoxybenzoin (10). Commercially available 3,4-difluorobenzaldehyde (12) and sodium thiomethoxide are mixed in a polar solvent such as acetonitrile or dimethylformamide to form 3-fluoro-4-methylthio-benzaldehyde (13). . Mixing a solution of an aldehyde, zinc iodide and trimethylsilyl cyanide in a halogenated solvent such as dichloromethane at room temperature gives trimethylsilyl cyanohydrin. Deprotonation of cyanohydrin with a base such as lithium diisopropylamide or lithium hexamethyl-disilylamide, followed by addition of the appropriately substituted benzyl halide and acid-base work-up of the reaction mixture to 1- (3-fluoro-4- Methylthiophenyl) -2- (substituted-phenyl) -ethanone (10
) Is obtained.

[0182]

[Chemical 59]

A synthetic scheme for the preparation of 3-fluoro-4-methylthiophenyl-substituted-phenyl-ethanones (11) with alternative regiochemistry is outlined in Scheme VI. Reduction of 3-fluoro-4-methylthio-benzaldehyde (13) with hydride reagents such as sodium borohydride, lithium aluminum hydride and the like gives benzyl alcohol. Conversion of benzyl alcohol to benzyl halide is accomplished by preparation of the tosylate followed by displacement with chloride or bromide ion (represented by X in Scheme VI). These compounds are
It can be utilized in the synthetic methodology previously described to obtain 1- (substituted-phenyl) -2- (3-fluoro-4-methylthiophenyl) -ethanone (11).

[0184]

[Chemical 60]

Scheme VII shows 3-fluoro-4-methylthio-benzaldehyde (13)
To 1- (substituted-phenyl) -2- (3-fluoro-4-methylthiophenyl)
-Exemplifies the methods that can be used to produce Ethanone (11). In step 1, aldehyde (13) and substituted phenylacetic acid (15) are heated in acetic anhydride and triethylamine and quenched with water to give 2,3-disubstituted acrylic acid (16). Acrylic acid (16) and diphenylphosphoryl azide (D
A mixture of PPA) and triethylamine produces an acrylic azide. The acrylic azide undergoes the Curtius transition to the isocyanate, which is captured by tert-butanol to give N-tert-butylcarboxy-carbamate. Treatment of the carbamate with concentrated hydrochloric acid provides the substituted ketone (11).

[0186]

[Chemical formula 61]

The preparation of 3,4-diarylthiophene (18) is illustrated in Scheme VIII. 3-fluoro-4-methylthiophenyl-substituted-phenyl-ethanone (
10) and the acetal of dimethylformamide are refluxed together in toluene. Removal of solvent and excess acetal gives the enamine (17). Refluxing the enamine (17) in thioacetic acid in 1,2-dichloroethane gives the Michael addition product (17a). The 1,2-dichloroethane is removed under reduced pressure, the residue is dissolved in an alcoholic solvent and the relevant sodium alkoxide is added. Mixing at room temperature yields the desired trisubstituted thiophene (18) after purification.

[0188]

[Chemical formula 62]

As illustrated in Scheme IX, the methylthio moiety (18) can be converted to the methyl sulfone and sulfonamide (19) as previously described. Thiophene (1
The ester group of 9) can then be manipulated into many functional groups such as alcohols, alkyls, alkenyls, alkynyls, amides, cyanos, etc. using conventional organic laboratory methods. The ester group can also be saponified and the resulting carboxylic acid (21) removed by copper mediated decarboxylic acid to give the 3-4 substituted diphenylthiophene (22).

[0190]

[Chemical formula 63]

Alternatively, as illustrated in Scheme X, the remaining hydrogens on the thiophene ring can be converted to halogens or nitro groups (23) and the ester converted to structures (24) and (2
Remanipulate various functional groups such as 5) as previously described.

[0192]

[Chemical 64]

3-Fluoro-4-methylthiophenyl-substituted-phenyl-ethanone (10)
Initiation of the thiophene protocol with the second regioisomer of and the execution of the thiophene chemistry described in Scheme X provides thiophenes with the positional substitution as shown in Scheme XI.

[0194]

[Chemical 65]

Synthetic Scheme XII illustrates the preparation of tetrasubstituted pyrazoles from acetophenone (29). In Step 1 of Synthetic Scheme XII, phenyl-methyl ketone (29) is treated with a base and an alkylating agent (R ³ L, where L represents a leaving group such as tosyl) to give a substituted ketone (30). Is obtained. In step 2, the substituted ketone (30) is treated with a base such as sodium methoxide and an ester (R ^3A CO ₂ CH ₃ ) or ester equivalent (R ^3A CO-imidazole) to give the intermediate diketone (31). Obtained [Reid, Calvin; Ame
r. Chem. Soc. , 72, 2948-2952 (1950)]. In step 3, the diketone (31) was substituted with hydrazine (in acetic acid or alcoholic solvent (
Reacting with 32) gives a mixture of pyrazoles (33) and (34). Separation of the desired pyrazole (34) can be accomplished by chromatography or recrystallization.

[0196]

[Chemical formula 66]

Synthetic Scheme XIII illustrates the preparation of 4-unsubstituted-pyrazole (ie, R ^3A used in Scheme XIII is hydrogen). In step 1, ketone (29) is treated with a base, preferably sodium methoxide or sodium hydride,
And treatment with an ester or ester equivalent forms the intermediate diketone (35), which is used without further purification. In step 2, treatment of the diketone (35) with the hydrochloride salt of the substituted hydrazine (32) or the free base at reflux for 10 to 24 hours in an anhydrous proton donating solvent such as absolute ethanol or acetic acid gives pyrazole (36) and A mixture of (37) is obtained. Recrystallization from diethyl ether / hexane or chromatography gives (37) (usually as a pale yellow or tan solid). Another pyrazole is US Pat. Nos. 5,401,765, 5,434,178, 4,146,721, 5,051,
518, 5,134,142 and 4,914,121, which are incorporated by reference herein, and can be prepared by suitable modification of the methods described therein.

[0198]

[Chemical formula 67]

Synthetic Scheme XIV shows an example method for making a 4,5-dihydrobenzo [g] indazole compound. In Step 1, the ethyl ester of acetate in a proton donating solvent such as methanol is mixed with a base such as 25% sodium methoxide and the 1-tetralone derivative (38) to give the intermediate diketone (
39) is obtained. In step 2, the diketone (39) is treated with the free base or hydrochloride salt of the substituted hydrazine (32) for 24 hours under reflux in an anhydrous proton donating solvent such as absolute ethanol or acetic acid to give pyrazole (40) and ( 41
A) mixture is obtained. Recrystallization was performed using 4,5-dihydrobenzo [g] indazole-
This gives benzenesulfonamide (40).

[0200]

[Chemical 68]

Synthetic Scheme XV illustrates the preparation of 4-chloro-pyrazole compound (42) from pyrazole compound (37). Chlorination occurs when a stream of chlorine gas is passed through the solution containing the pyrazole compound (37) at room temperature.

[0202]

[Chemical 69]

Synthetic Scheme XVI illustrates another regioselective method of making pyrazole (37). The commercially available enone (43) can be epoxidized to give the epoxy ketone (44), which is treated with 3-fluoro-4-sulfonamidophenylhydrazine hydrochloride to give the pyrazole (37).

[0204]

[Chemical 70]

Scheme XVII illustrates a regioselective method of making methylthiopyrazole (49). Difluoro-acetophenone (45) is mixed with sodium thiomethoxide in a polar solvent such as acetonitrile or dimethylformamide to give 3-fluoro-4-methylsulfonylacetophenone (46). Acetophenone (46) is mixed with a base such as sodium methoxide and an acylating agent such as an ester (R ¹ CO ₂ CH ₃ ) or an activated ester equivalent (R ¹ CO-imidazole) to form an intermediate diketone ( 48) is obtained [J. A
mer. Chem. Soc. , 72, 2948-2952 (1950)]. Refluxing this diketone (48) with a substituted hydrazine in an alcoholic solvent under acidic conditions gives methylthiopyrazole (49) after chromatography or crystallization.

[0206]

[Chemical 71]

Methylthiopyrazole (49) can be converted to 3-fluoro-4-methylsulfonylpyrazole or 3-fluoro-4-methylsulfonamidylpyrazole (50) using the methods previously described. Similar pyrazoles are described in US Pat.
86,534 (incorporated herein by reference).

WO 96/37476 describes a method for the preparation of 3-haloalkyl-1H-pyrazoles and is incorporated herein by reference.

[0209]

[Chemical 72]

Synthetic Scheme XIX illustrates a method that can be used to prepare the oxime intermediate (52). Treatment of the ketone intermediate (51) with hydroxylamine (generally prepared from hydroxylamine hydrochloride with sodium acetate) provides the oxime intermediate (52). A wide range of solvents can be used, including ethanol, toluene and tetrahydrofuran.

[0211]

[Chemical formula 73]

Synthetic Scheme XX illustrates a method that can be used to prepare the hydrated isoxazole derivative (53). Treatment of the substituted oxime (52) with at least 2 equivalents of a base such as n-butyllithium produces a dianion, which is subsequently acylated. Suitable acylating agents include anhydrides, acyl imidazoles and esters. Quenching of the reaction mixture with dilute aqueous acid allows the hydrated isoxazole derivative (53) to be isolated after crystallization or chromatography.

[0213]

[Chemical 74]

Synthetic Scheme XXI illustrates a method that can be used to prepare the isoxazole analog (54) via dehydration of the hydrated isoxazole derivative (53). Dissolution of the substituted hydrated isoxazole derivative (53) in a suitable solvent such as toluene and treatment with a stoichiometric amount of sulfuric acid from the catalyst achieves dehydration, thereby producing the isoxazole derivative (54). Other acids such as concentrated HCl, concentrated HBr and many other acids can also be used to achieve this conversion.

[0215]

[Chemical 75]

Synthetic Scheme XXII shows the corresponding 3-fluorophenylisoxazole (5
Illustrates a method that can be used to prepare the substituted 3-fluoro- (4-sulfonamidyl) phenylisoxazole analog (55) from 4). The process is a two step process for the direct introduction of sulfonamide moieties into 3-fluorophenylisoxazole (54) or hydrated isoxazole (53). In step 1, isoxazole (54) or hydrated isoxazole (53) is treated with 2 or 3 equivalents of chlorosulfonic acid at 0 ° C. to form the corresponding sulfonyl chloride. Treatment of the sulfonyl chloride so formed in step 2 with concentrated ammonia provides the sulfonamide derivative (55).

[0217]

[Chemical 76]

Synthetic Scheme XXIII illustrates the three-step process used to prepare 3-fluoro-4-sulfonamidyl-phenylisoxazole (55) from 3-fluorophenylisoxazole (54). In Step 1, 3-fluorophenylisoxazole (54) is treated with sulfur trioxide pyridine complex at about 100 ° C. to convert to the corresponding sulfonic acid. In step 2, sulfonic acid is converted to sulfonyl chloride by the action of phosphorus oxychloride. Treatment of the sulfonyl chloride with concentrated ammonia in Step 3 provides the sulfonamidyl-phenylisoxazole (55).

[0219]

[Chemical 77]

Scheme XXIV illustrates a five-step process for making substituted isoxazole derivatives. In Step 1, the substituted 1-substituted phenyl-2 (3-fluoro-4-methylthiophenyl) -ethanone (11) was treated with hydroxylamine hydrochloride in the presence of sodium acetate in aqueous ethanol to give the oxime (56
) Is converted to. Reaction of the oxime (56) with slightly more than 2 equivalents of n-butyllithium and subsequent quenching of the resulting dianion with a suitable acylating agent such as anhydrides, acid chlorides, esters and imidazoles results in hydration. This gives isoxazole (57). In the last step, the hydrated isoxazole is dehydrated with acid and the sulfonamide is unmasked by treatment with aqueous sulfuric acid to form the isoxazole derivative (58).

[0221]

[Chemical 78]

The methyl sulfide moiety (58) prepared in Scheme XXIV is a sulfonamide or a methyl sulfone diarylisoxazole (58) as previously described.
59) can be converted.

[0223]

[Chemical 79]

Scheme XXVI illustrates a three-step process for the preparation of another isoxazole isomer. In step 1, the substituted 1,2-diphenylbutenone (60) is converted to the oxime (61) by treatment with hydroxylamine hydrochloride in the presence of sodium acetate in aqueous ethanol. Oxime (61) is reacted with potassium iodide and iodine in the presence of base such as sodium hydrogen carbonate to give the halo intermediate. Addition of sodium bisulfite forms the isoxazole (62).

[0225]

[Chemical 80]

Treatment of isoxazole (62) with chlorosulfonic acid provides, after work-up, the intermediate sulfonyl chloride, which can be converted to sulfonamide (63) by mixing with ammonia in various solvents. In addition, diaryl / heteroaryl isoxazoles containing a 3-fluoro-4-sulfonamidyl-phenyl moiety are disclosed in PCT Application No. US96 / 01869, PCT Document WO92 / 051.
62 and WO 92/19604, and European Patent Publication EP 26928, which are incorporated herein by reference, and can be prepared.

[0227]

[Chemical 81]

Scheme XXVIII illustrates a synthetic route for furanone production. Acetophenone (46) is halogenated in acetic acid to give the acyl halide (64). Displacement of the halide (64) with phenylacetic acid (65) in the presence of triethylamine in acetonitrile, followed by addition of diazobi-cyclo [5.4.0] undec-7-ene gives the furanone (66) [Ahluwalia , Synt
h. Commun. 19, 619-626 (1989)].

[0229]

[Chemical formula 82]

Methylthiofuranone (66) can be converted to methylsulfonyl or sulfonamide furanone (67) as previously described.

[0231]

[Chemical 83]

Furan (68) can be prepared from furanone (66) by re-aromatization via reduction and dehydrogenation. Furanone (6) with a hydrogenating reagent such as diisopropyl aluminum hydride (DIBAL-H) at low temperature in a chlorinated solvent such as dichloromethane.
Treatment of 6) followed by treatment with a mineral acid to catalyze the dehydration of the resulting hemiacetal gives furan (68) [Singh, Indian J Chem, S.
ect B. , 29,954-960 (1990)]. Sulfides can be converted to sulfones (69) and sulfonamides (70) as previously described.

[0233]

[Chemical 84]

Scheme XXXI illustrates the preparation of substituted diaryl imidazoles (76) containing a 3-fluoro-4-sulfonylphenyl moiety. Displacement of 4-fluorine in 3,4-difluoro-nitrobenzene (71) with sodium thiomethoxide provides 3-fluoro-4-methylthio-nitrobenzene (72). Reduction of the nitro group to an amine can be accomplished by hydrogenation with a metal catalyst such as palladium or platinum on various supports. The resulting phenylamine (73) can be reacted with a substituted nitrile in the presence of an alkylaluminum reagent such as trimethylaluminum in an inert solvent such as toluene or benzene to give the amidine (74). Mixing of amidine (74) with 2-haloketone in a solvent such as acetone, acetonitrile or dimethylformamide in the presence of a mild inorganic or organic base such as triethylamine, diisopropylamine or sodium hydrogen carbonate is 4
, 5-dihydroimidazole, which can be dehydrated in the presence of catalytic mineral acids,
This gives the 2-disubstituted imidazole (75).

These types of diaryl / heteroaryl imidazoles are also disclosed in US Pat. No. 4,822,805 and PCT documents WO 93/14082 and WO 96/0.
It can also be made according to the methods described in 3388, which are incorporated herein by reference. The methyl sulfide can then be converted to the sulfone or sulfonamide as previously described to give the substituted diaryl imidazole (76).

[0236]

[Chemical 85]

Commercially available 4-bromo-2-fluorobenzenesulfonyl chloride (77) can be treated with sodium sulfite followed by dimethylsulfate treatment to give 4
Gives -Bromo-2-fluoromethylsulfonyl-benzene (78) [Org
anic Synthesis, Volume IV, p. 674]. Diaryl / heteroarylcyclopentenes containing orthofluorosulfonyl functional groups (82
) In U.S. Pat. No. 5,344,991 and PCT document WO95 / 00501.
4-Bromo-2 as described in Scheme XXXII according to the methods described in (these are incorporated herein by reference).
It can be prepared from -fluoromethylsulfonyl-benzene (78). The sulfone can be converted to the cyclopentenephenyl sulfonamide (83) as previously described.

[0238]

[Chemical 86]

Scheme XXXIII is similar to the Suzuki coupling method [Synth. Com
mun. , 11,513 (1981)], using 1,2-diarylbenzenes (87) containing orthofluorosulfonyl functional groups from bromo-biphenyl intermediates (86) using appropriately substituted phenylboronic acids. 7 illustrates a method for. The bromo-biphenyl intermediate (86) can be prepared in a similar manner to the method described in Scheme XXXII. Sulfonamides can be prepared from sulfones as described at the beginning of this application. US Patent Application No. 08 / 346,53
3 generally describes the preparation of terphenyl compounds, which is incorporated herein by reference.

[0240]

[Chemical 87]

Scheme XXXIV illustrates the preparation of 3,4-diaryloxazol-2-one (91) and its derivatives. Oxidation of the methyl group adjacent to the carbonyl carbon of 3-fluoro-4-methyl-sulfonylacetophenone (46) to an alcohol can be accomplished using a base, Aliquat 336 and oxygen (see eg EP197704). Treatment of the resulting alcohol (88) with an isocyanate, followed by dehydration of the hydroxy intermediate (89) in the presence of acid gives the oxazolone (90). The methyl sulfide of oxazolone (90) can be converted to a sulfone or sulfonamide as previously described to give a substituted 3,4-diaryloxazol-2-one (91). Other 3,4-diaryloxazol-2-one compounds containing substituted 3,4-diaryloxazol-2-ones containing orthofluorosulfonyl functional groups are described in PCT Documents WO 98/11080 and W.
2-Hydroxy-1 ′-[3′-fluoro-4 according to the method described in O99 / 14205, which is incorporated herein by reference.
-Methylsulfide phenyl] -ethanone (88).

[0242]

[Chemical 88]

Scheme XXXV illustrates the preparation of 3,4-diarylthiazolin-2-ones. Mixing analine (92) with bis (ethoxythiocarbonyl) in an alcoholic solvent gives ethylthiocarbamate (93). Ethylthiocarbamate (93) and 2-bromoacetophenone (64) in ethereal solvent
Refluxing provides the hydroxy intermediate (94). Heating the hydroxy intermediate (94) with a mineral acid in an alcoholic solvent gives the desired 3,4-diarylthiazoline-
2-one (95) is obtained. US Pat. No. 5,859,036 describes another method that can be suitably modified and used to make the present compounds. US Pat. No. 5,859,036 is incorporated herein by reference. Methyl-sulfide (95) can be converted to the corresponding sulfone or sulfonamide as previously described to give the substituted 3,4-diarylthiazolin-2-ones (96).

[0244]

[Chemical 89]

Scheme XXXVI is 3,4-diarylthiazoline-2-thione (100)
Exemplifies the manufacture of Mixing analine (92) with carbon disulfide in an alcoholic solvent gives the dithiocarbamate (97). Reflux of dithiocarbamate (97) and 2-bromoacetophenone (64) in an ethereal solvent provides the hydroxy intermediate (98). Hydroxy intermediate (98
) And mineral acid upon heating the desired 3,4-diarylthiazoline-2-thione (9
9) is obtained. US Pat. No. 5,859,036 illustrates a similar process and is incorporated herein by reference. Methyl-sulfide (
99) can be converted to the corresponding sulfone or sulfonamide as previously described to give the substituted 3,4-diarylthiazoline-2-thiones (96).

WORKING EXAMPLES The following examples contain detailed descriptions of the methods of making compounds of Formulas I-VII. These detailed descriptions are within the scope of the present invention and serve as illustrations of the above general synthetic methods which form part of the present invention. These detailed descriptions are provided for illustrative purposes only and are not intended as limitations on the scope of the invention. Unless otherwise noted, all percentages are by weight and temperatures are in degrees Celsius. The NMR spectra of all compounds shown are consistent with their assigned structure.

The following abbreviations were used: HCl-DMSO hydrochloride-dimethylsulfoxide DMSOd ₆ -deuterated dimethylsulfoxide CDCl ₃ -deuterated chloroform MgSO ₄ -magnesium sulphate NaHCO ₃ -sodium hydrogencarbonate KHSO ₄ -sodium hydrogensulfate DMF - dimethylformamide NaOH - sodium hydroxide BOC - tert - butyloxycarbonyl CD ₃ OD - deuterated methanol EtOH - ethanol LiOH - lithium hydroxide CH ₂ Cl ₂ - methylene chloride h - time hr - hours min - minutes THF - tetrahydrofuran TLC - thin layer chromatography Et ₃ N - triethylamine DBU - 1,8-diazabicyclo [5.4.0] undec-7-ene DMAP - 4-dimethylamino-pin Jin Example 1

[0248]

[Chemical 90]

2-Fluoro-4- (4-phenyl-3-thienyl) benzenesulfonamide

[0250]

[Chemical Formula 91]

Step 1: Preparation of 3-fluoro-4- (methylthio) -benzaldehyde 3,4-Difluorobenzaldehyde (52.1 g, 0.36 mol) was dissolved in acetonitrile (500 mL). Sodium thiomethoxide (25.6g,
0.36 mol) was divided into 4 equal parts and added at 15 minute intervals. The slightly exothermic reaction solution was stirred at room temperature for 4 hours. The reaction mixture was added to ethyl acetate (500 mL)
) And washed with saturated sodium bicarbonate (2 × 200 mL), followed by saturated ammonium chloride (2 × 100 mL). The solution was dried over sodium sulfate and the solvent removed under reduced pressure. 3-fluoro-4- (methylthio) -benzaldehyde (3
8.5 g, 0.22 mol) was isolated as a clear liquid by vacuum distillation (135-145 ° C at 25 mmHg). ESHRMS m / z 171.0302 (M
Calculated as + H, 171.0280).

[0252]

[Chemical Formula 92]

[0253] Step 2: 3-fluoro-4- (methylthio) - □ - [(trimethylsilyl) Oki sheet] - benzenepropanoic acetonitrile 3-fluoro-4-methylthio - benzaldehyde (33.0 g, 194.0
Mmol), trimethylsilyl cyanide (19.8 g, 200 mmol) were mixed together in dichloromethane (350 mL) and zinc iodide (35 mg) was added. The solution was heated at 35 ° C. The bath was removed and the solution was stirred for 1 h, during which an exotherm was observed. After cooling to room temperature, the solvent was removed under reduced pressure and 3-fluoro-4- (methylthio)-□-[(trimethylsilyl) oxy] -benzeneacetonitrile (
51.6 g, 192 mmol) were obtained as a yellow oil (98% yield):

[0254]

[Chemical formula 93]

ESHRMS m / z 261.0769 (calculated as M + H, 261.07
49).

[0256]

[Chemical 94]

[0257] Step 3: 1- [3-fluoro-4- (methylthio) - phenyl] -2-phenylacetic ethanone tetrahydrofuran (400 mL), 3-fluoro-4- (methylthio) -
□-[(Trimethylsilyl) oxy] -benzeneacetonitrile (40.1 g,
149 mmol) was cooled to -78 ° C. Lithium hexamethyldisilazide (
A 1.0 M hexane solution (175 mL, 175 mmol) was added dropwise over 1 hour. The solution was stirred for an additional hour at -78 ° C. Benzyl bromide (24.5
g, 149 mmol) as a solution in tetrahydrofuran (100 mL) was added dropwise over 25 minutes. The solution was kept at -78 ° C for 1 hour, warmed to room temperature and allowed to reach room temperature 6
Maintained for hours. The solution was poured into ethyl acetate (300 mL). 1N hydrochloric acid (200m
L) was added and the solution was stirred at room temperature for 48 hours. The layers were separated and the organic layer was collected. The organic layer was mixed with 15% aqueous sodium hydroxide solution and stirred for 30 minutes. The organic layers were combined, washed with saturated ammonium chloride (200 mL), the solution was dried over sodium sulfate, and the solvent was removed under reduced pressure to give a yellow oil. The product was isolated by preparative silica chromatography followed by crystallization from 2% ethyl acetate and hexane (400 mL). 1- [3-fluoro-4- (methylthio) phenyl]-
2-Phenylethanone (21.5 grams, 82.0 mmol) was obtained as white crystals (55% yield): Mp 77.1-77.2 ° C.

[0258]

[Chemical 95]

[0259]

[Chemical 96]

[0260] Step 4: Methyl 3- [3-fluoro-4- (methylthio) phenyl] -4-off Eniru thiophenecarboxylic-carboxylate 1- [3-fluoro-4- (methylthio) phenyl] -2 Phenylethanone (21.9 g, 81.5 mmol) and dimethylformamide dimethyl acetal (41.3 g, 347 mmol) were refluxed in toluene (200 mL) for 16 hours. The yellow solution was cooled to room temperature and the solvent was removed under reduced pressure. The yellow oil obtained was dissolved in 50% ethyl acetate / 50% hexane (200 mL) and suction filtered through silica gel. Silica is 50% ethyl acetate / 50% hexane (15%
It was washed with 0 mL). The filtrates were combined and the solvent was removed under reduced pressure to give 25.19 g of enamine (shown below) as a yellow oil.

[0261]

[Chemical 97]

Enamine (25.09 g, 79.3 mmol) and methyl thio-glycolate (35.5 g, 326 mmol) were refluxed for 16 hours. The solvent was removed under reduced pressure, and the obtained residue was dissolved in methanol (300 mL). A 25% sodium methoxide methanol solution (75.0 mL, 326 mmol) was added, and the reaction solution was stirred. After stirring for 20 minutes, a precipitate formed and mixing was stopped. Solution is at room temperature 6
Hold the time and collect the crystals. Methyl 3- [3-fluoro-4- (methylthio) phenyl] -4-phenyl-2-thiophenecarboxylate (18.3 grams,
51.7 mmol) was isolated as white crystals. 200 mg was recrystallized from ethyl acetate and hexane to obtain analytical data, the rest was used without further purification (yield 64%): Mp 140.6-141.0 ° C.

[0263]

[Chemical 98]

ESHRMS m / z 359.0598 (calculated as M + H ⁺ , 359.0).
576).

[0265]

[Chemical 99]

Step 5: Preparation of methyl 3- [3-fluoro-4- (methylsulfinyl) phenyl] -4-phenyl-2-thiophenecarboxylate 3- [3-Fluoro-4- (methylthio) phenyl] -4 -Phenyl-2-thiophenecarboxylate (5.00 g, 13.9 mmol) was dissolved in dichloromethane (100 mL) and methanol (30 mL). Magnesium monoperoxyphthalate hexahydrate (MMPP) (80% 3.78 g, 7.6 mmol) was added in five equal portions at 1 minute intervals. The resulting heterogeneous solution was stirred for 1 hour. Additional MMPP (600 mg, 1.6 mmol) was added and the solution was stirred for 15 minutes. The reaction is complete and the solution is saturated sodium bicarbonate (2 x 100 mL).
It was extracted with. The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. Methyl 3- [3-fluoro-4- (methylsulfinyl) phenyl] -4-phenyl-2-thiophenecarboxylate was isolated by crystallization from dichloromethane and hexane (81% yield): Mp164.0-. 164.1 ° C.

[0267]

[Chemical 100]

ESHRMS m / z 375.0536 (calculated as M + H, 375.05
25).

[0269]

[Chemical 101]

[0270] Step 6: Methyl 3- [4 - [[(acetyloxy) - methyl] thio] -3-off Ruorofeniru] -4-phenyl-2-thiophene-carboxylate Methyl 3- [3-fluoro-4 -(Methylsulfinyl) phenyl] -4-
Phenyl-2-thiophenecarboxylate (4.13 g, 11.04 mmol) was dissolved in acetic anhydride (45.0 mL). Powdered sodium acetate (4.0 g,
48.7 mmol) was added and the solution was refluxed for 8 hours. The solution was poured into a 500 mL round bottom flask and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and dichloromethane (20 mL). The solution was saturated with sodium hydrogen carbonate (
3 × 100 mL) followed by saturated ammonium chloride (2 × 100 mL). The solvent was removed under reduced pressure, the residue was dissolved in ether, dried over sodium sulfate,
The solvent was removed under reduced pressure. Methyl 3- [4-[[(acetyloxy) -methyl] thio] -3-fluorophenyl] -4-phenyl-2-thiophenecarboxylate (2.9 g, 6.90 mmol) was obtained from diethyl ether and hexane. Isolated as white crystals by crystallization. (Yield 62%). Mp102.9
-103.7 ° C.

[0271]

[Chemical 102]

ESHRMS m / z 434.00898 (calculated as M + NH ₄ ⁺ , 434.
0896).

[0273]

[Chemical 103]

[0274] Step 7: Methyl 3- [4 - [[(acetyloxy) methyl] - sulfonyl] - 3-fluorophenyl] -4-phenyl-2-thiophenecarboxylate manufacturing methyl 3- [4 - [[ (Acetyloxy) -methyl] thio] -3-fluorophenyl] -4-phenyl-2-thiophenecarboxylate (3.56 g, 8
． 55 mmol), MMPP (5.80 g of 80%, 9.45 mmol) were mixed in methanol (30 mL) and dichloromethane (100 mL). The solution was mixed at room temperature for 16 hours and additional MMPP (2.00 g) was added. The solution was heated to reflux for 8 hours. The solution was poured into ethyl acetate (200 ml) and extracted with saturated aqueous sodium hydrogen carbonate solution (2 x 100 mL), followed by brine (100 mL). The organic layers were collected and the solvent was removed under reduced pressure. The white semi-solid obtained was triturated with ethyl acetate and hexane. Methyl 3- [4-[[(acetyloxy) methyl] -sulfonyl] -3-fluorophenyl] -4-phenyl-2-thiophenecarboxylate (3.15 g, 7.03 mmol) was isolated as a white solid. Was done. (Yield 8
2%). Mp 164.7-164.8 ° C.

[0275]

[Chemical 104]

ESHRMS m / z 466.0796 (calculated as M + NH ₄ ⁺ , 466.
0794).

[0277]

[Chemical 105]

[0278] Step 8: 2-Methyl 3- (3-fluoro-4-sulfinophenyl) -4-off Eniru thiophenecarboxylic-carboxylate Methyl 3- [4 - [[(acetyloxy) methyl] - Sulfonyl] -3-fluorophenyl] -4-phenyl-2-thiophenecarboxylate (2.75 g
, 6.13 mmol) was dissolved in tetrahydrofuran (100 mL) and stirred at room temperature. Add 25% sodium methoxide methanol solution (3.0 mL),
The solution was stirred for 5 minutes. Pour the resulting slurry into ethyl acetate (200 mL), 1
An aqueous solution of N hydrochloric acid (100 mL) was added. The solution was stirred and the layers were separated. The organic layers were collected and the aqueous layer was back extracted with ethyl acetate (100 mL). The organic layers were combined, extracted with brine, dried over sodium sulfate, and the solvent removed under reduced pressure. 2-methyl 3
-(3-Fluoro-4-sulfinophenyl] -4-phenyl-2-thiophenecarboxylate (1.87 g, 4.59 mmol) was isolated as a white solid (77% yield). 6-133.1 ° C.

[0279]

[Chemical formula 106]

ESHRMS m / z 394.0586 (calculated as M + NH ₄ ⁺ , 394.
0583).

[0281]

[Chemical formula 107]

Step 9: Preparation of methyl 3- [3-fluoro-4- (sulfonamido) phenyl] -4 -phenyl-2-thiophenecarboxylate 2-Methyl 3- (3-fluoro-4-sulfinophenyl) -4-Phenyl-2-thiophenecarboxylate (1.51 g, 4.01 mmol) was dissolved in methanol (25 mL). Upon addition of water (10 mL), the solution became slightly cloudy. Sodium acetate (2.62 g, 32.0 mmol) and hydroxylamine-O-sulfonic acid (1.80 g, 16.6 mmol) were mixed together at room temperature for 4 hours. The solution was poured into ethyl acetate (100 mL) and 1N aqueous hydrochloric acid solution (2x5
0 mL), water (2x50 mL), saturated sodium bicarbonate (2x50 mL) and brine (50 mL). The solution was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Methyl 3- [3-fluoro-4- (sulfonamido) phenyl] -4-phenyl-2-thiophene-carboxylate (1.04 g, 2.
65 mmol) was isolated as a white solid by crystallization from ethyl acetate and hexane. (Yield 66%). Mp 168.3-168.4 ° C.

[0283]

[Chemical 108]

ESHRMS m / z 409.0684 (calculated as M + NH ₄ ⁺ , 409.
0692).

[0285]

[Chemical 109]

[0286] Step 10: 3- [3-fluoro-4- (sulfonamido) - phenyl] -4-off Eniru thiophenecarboxylic prepared methyl 3- [3-fluoro-4- (sulfonamido) carboxylic acid phenyl ] -4-Phenyl-2-thiophene-carboxylate (922 mg, 2.35 mmol) and lithium hydroxide (356 mg, 8.00 mmol) in tetrahydrofuran (14.0 mL), methanol (4.0 mL) and water ( 2.0 mL) at room temperature for 16 hours. The solution was poured into ethyl acetate (100 mL) and extracted with 1N aqueous hydrochloric acid solution (2 x 50 mL) followed by brine (50 mL). The solution was dried over sodium sulfate and the solvent removed under reduced pressure. 3- [3-Fluoro-4- (sulfonamido) -phenyl] -4-phenyl-2-thiophenecarboxylic acid (723 mg, 2
． 14 mmol) was isolated as a white solid by crystallization from ethyl acetate and hexane. (Yield 91%). Mp 214.6-214.7 ° C.

[0287]

[Chemical 110]

ESHRMS m / z 395.0522 (calculated as M + NH ₄ ⁺ , 395
． 0536).

[0289]

[Chemical 111]

[0290] Step 11: 2-Fluoro-4- (4-phenyl-3-thienyl) of 3- benzenesulfonyl N'amido [3-fluoro-4- (sulfonamido) - phenyl] -4-phenyl -
2-Thiophenecarboxylic acid (331 mg, 0.87 mmol) and copper powder (1
50 mg) was heated in freshly distilled quinoline (15 mL) to 160 ° C. for 1 hour. The reaction solution was cooled to room temperature and poured into ethyl acetate (100 mL). It was extracted with 1N aqueous hydrochloric acid solution (2 x 100 mL), saturated sodium hydrogen carbonate (2 x 100 mL) and brine (100 mL). The solution was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Thiophene (113 mg, 0.34 mmol) was isolated as a white solid by flash chromatography (ethyl acetate / hexane), followed by crystallization from diethyl ether and hexane. (Yield 38%).
Mp 170.9-171.0 ° C.

[0291]

[Chemical 112]

ESHRMS m / z 351.0647 (calculated as M + NH ₄ ⁺ , 351.
0367). Example 2

[0293]

[Chemical 113]

[0294] 3- [3-fluoro-4- (methylsulfonyl) phenyl] -4-phenylthio Fen

[0295]

[Chemical 114]

Step 1: Preparation of methyl 3- [3-fluoro-4- (methylsulfonyl) phenyl] -4-phenyl-2-thiophenecarboxylate Methyl 3- [3-fluoro-4- (methylthio) phenyl]- 4-Phenyl-2-thiophenecarboxylate (5.15 g, 14 mmol, Example Step 4)
Was dissolved in dichloromethane (100 mL) and methanol (30 mL). Magnesium monoperoxyphthalate hexahydrate (MMPP) (80%
(10.25 g, 17 mmol) was added in 5 equal portions at 1 minute intervals. The resulting heterogeneous solution was stirred overnight at room temperature. Ethyl acetate (200 mL) was added and the solution was extracted with saturated sodium hydrogen carbonate (2 x 100 mL). The organic layer was dried over sodium sulfate and the solvent was removed under vacuum. Methyl 3- [3-fluoro-4- (methylsulfonyl) phenyl] -4-phenyl-2-thiophenecarboxylate (5.27 g, 12.9 mmol) was isolated by crystallization from ethyl acetate and hexane. It was (Yield 92%): mp181-182 ° C.

[0297]

[Chemical 115]

ESHRMS m / z 408,0738 (calculated as M + H ⁺ , 408.0.
740). Elemental analysis, calculated for C ₁₉ H ₁₅ FO ₄ S ₂ : C, 58.45; H, 3
． 87; Found: C, 58.22; H, 3.78.

[0299]

[Chemical formula 116]

[0300] Step 2: 3- [3-fluoro-4- (methylsulfonyl) phenyl] -4-phenyl-2-thiophene prepared methyl 3-carboxylic acid [3-fluoro-4- (methylsulfonyl) phenyl] -4-Phenyl-2-thiophenecarboxylate (2.46 g, 63 mmol) in tetrahydrofuran (25 mL), methanol (175 mL) and water (50 mL)
) Dissolved in. Lithium hydroxide (0.66 g, 157 mmol) was added and the mixture was stirred at room temperature overnight. The organic solvent was removed under vacuum and the aqueous suspension was washed with ethyl acetate (
100 mL). The solution is 10% aqueous hydrochloric acid (2X100 mL), water (2X
100 mL), extracted with saturated ammonium chloride (2 × 100 mL) and dried over sodium sulfate. The solvent was removed under vacuum and 3- [3-fluoro-4- (methylsulfonyl) phenyl] -4-phenyl-2-thiophenecarboxylic acid (2.12
g, 56.0 mmol) was obtained by crystallization from ethyl acetate and hexane.
(Yield 90%): mp216-218 ° C.

[0301]

[Chemical 117]

ESHRMS m / z 394,0539 (calculated as M + NH ₄ ⁺ , 394.
0583). Elemental _{analysis, C 18 H 13 FO 4 S} 2 Calculated: C, 57.43; H,
3.48; Found: C, 56.94; H, 3.41.

[0303]

[Chemical 118]

[0304] Step 3: 3- [3-fluoro-4- (methylsulfonyl) phenyl] -4--phenyl thiophene 3- [3-fluoro-4- (methylsulfonyl) phenyl] -4-phenyl -
2-Thiophenecarboxylic acid (1.02 g, 3 mmol) was dissolved in freshly distilled quinoline (10 mL) and powdered copper (0.09 g, 1.3 mmol) was added. The reaction solution was heated to 130 ° C. for 3 hours. The reaction solution was cooled to room temperature and 10% hydrochloric acid (50
mL) and ethyl acetate (50 mL). The solution is a 10% aqueous hydrochloric acid solution (2x
50 mL), water (2X50 mL), saturated ammonium chloride (2X50 mL) and dried over sodium sulfate. 3- [3-Fluoro-4- (methylsulfonyl) phenyl] -4-phenylthiophene (0.55 g, 1.60 mmol) was purified by preparative silica chromatography followed by crystallization from ethyl acetate and hexane. Isolated. (Yield 54%): mp 140-141 ° C.

[0305]

[Chemical formula 119]

ESHRMS m / z 350.0686 (calculated as M + NH ₄ ⁺ , 350.
0685). Elemental _{analysis, C 17 H 13 FO 2 S} 2 Calculated: C, 61.42; H,
3.94; Found: C, 61.44; H, 3.94. Example 3

[0307]

[Chemical 120]

4- [5- (3-chloro-4-methylphenyl) -3- (difluoromethyl) -1H-pyrazol-1-yl] -2-fluorobenzenesulfonamide

[0309]

[Chemical 121]

Step 1: Preparation of 1- (3-chloro-4-methylphenyl) -ethanone 3'-chloro-4'-methylacetophenone (26.8 g, 200 mmol).
And aluminum chloride (80.0 g, 600 mmol) in chloroform (20
0 mL) with stirring at room temperature while chlorine gas (14.2 g, 200 mmol) was added.
Was added over 30 minutes. The reaction solution was stirred at room temperature for 2 hours. The mixture was poured onto ice and extracted with ethyl acetate (3X100mL). The combined organic extracts were washed with 10% aqueous hydrochloric acid (2 x 100 mL) and water (2 x 100 mL). The resulting solution was dried over magnesium sulfate and concentrated. 1- (3-Chloro-4-methylphenyl) ethanone was purified by distillation at 0.1T, 78-95 ° C and formed a pale yellow solid on standing. This material was used in the next step without further purification or characterization.

[0311]

[Chemical formula 122]

Step 2: Preparation of 1- (3-chloro-4-methylphenyl) -4,4-difluoro -1,3 -butanedione 1- (3-chloro-4-methylphenyl) ethanone (7.60 g, 45 mmol), ethyl difluoroacetate (6.20 g, 50 mmol) and sodium methoxide (14 mL) were stirred in diethyl ether (50 mL) at room temperature for 5 hours. Ethyl acetate (50 mL) was added to the reaction solution, and a 10% aqueous hydrochloric acid solution (2 x 50 mL was added.
), Water (2X50 mL), saturated ammonium chloride (2X50 mL), and dried over sodium sulfate. Removal of the solvent under vacuum gave a yellow solid,
1- (3-chloro-4-methylphenyl) -4,4-difluoro-1,3-butanedione (4.95 g, 20.2 mmol, 45% yield): mp 40-41 ° C.

[0313]

[Chemical 123]

ESHRMS m / z 246.0286 (calculated as M + H ⁺ , 246.0
259). Elemental analysis, calculated for C ₁₁ H ₉ F ₂ ClO ₂ : C, 53.57; H,
3.68; Found: C, 53.10; H, 3.51.

[0315]

[Chemical formula 124]

Step 3: Preparation of 2,4-difluorobenzenesulfonamide 2,4-difluorobenzenesulfonyl chloride (50.26 g, 237 mmol) and concentrated ammonium hydroxide (100 mL) in methylene chloride (800 mL).
And were stirred at room temperature for 2 hours. Methylene chloride was removed under vacuum and the solid was dissolved in ethyl acetate (800 mL). The solution was extracted with water (2X500 mL), saturated ammonium chloride (2X500 mL) and dried over sodium sulfate. The solvent was removed under vacuum and 2,4-difluorobenzenesulfonamide was obtained by crystallization from ethyl acetate and hexane (43.27 g, 225 mmol, yield 9).
5%): mp155-156 ° C.

[0317]

[Chemical 125]

ESHRMS m / z 192.9990 (calculated as M + H ⁺ , 193.0
009). Elemental analysis, calculated as C ₆ H ₅ F ₂ NO ₂ S: C, 37.31; H, 2
． 61; N, 7.25; Found: C, 37.38; H, 2.51; N, 7.26.
.

[0319]

[Chemical formula 126]

Step 4: Preparation of 2-fluoro-4-hydrazinobenzene-sulfonamide 2,4-Difluorobenzenesulfonamide (23.43 g, 121 mmol) and anhydrous hydrazine (17.00 g, 364 mmol) in acetonitrile ( Reflux in 300 mL) for 2 hours. The solvent was removed under vacuum and the solid was vigorously stirred in ethyl acetate (200 mL) overnight. The solid was filtered off and discarded and ethyl acetate was removed under vacuum to give a white solid. 2-Fluoro-4-hydrazinobenzene-sulfonamide (6.05 g, 29,5 mmol) was obtained by preparative silica chromatography followed by crystallization from ethyl acetate and hexane (yield 24%. ): Mp 136-137 ° C.

[0321]

[Chemical 127]

ESHRMS m / z 206.0451 (calculated as M + H ⁺ , 206.0
400). Elemental _{analysis, C 6 H 8 FN 3 O} 2 S Calculated: C, 35,13; H, 3
． 93; N, 20.48; found: C, 35.18; H, 3.85; N, 20,
29.

[0323]

[Chemical 128]

[0324] Step 5: 4- [5- (3-chloro-4-methylphenyl) -3- (Jifuruorome chill)-1H-pyrazol-1-yl] -2-fluoro-benzenesulfonamide Using 2- fluoro - 4-hydrazinobenzene-sulfonamide (0.73 g, 4.
0 mmol) was dissolved in ethanol (10 mL) and concentrated hydrochloric acid (0.5 mL) was added. After stirring at room temperature for 5 minutes, 1- (3-chloro-4-methylphenyl) -4,4-
Difluoro-1,3-butanedione (1.08 g, 4 mmol) was added and the reaction was refluxed for 1 hour. The solution was cooled to room temperature and water was added until the reaction became cloudy. 4- [5- (3-chloro-4-methylphenyl) -3- (difluoromethyl)
-1H-pyrazol-1-yl] -2-fluorobenzenesulfonamide (0.
88 g, 2.12 mmol) was isolated as pale orange crystals by direct suction filtration from the reaction mixture. (0.88 g, yield 53%): mp160-
161 ° C.

[0325]

[Chemical formula 129]

ESHRMS m / z 416.0465 (calculated as M + H ⁺ , 416.0.
447). Elemental _{analysis, C 17 H 13 ClF 3 N} 3 O 2 S Calculated: C, 49.10
H, 3.15; N, 10.11; Found: C, 49.09; H, 2.97; N.
, 9.95. Example 4

[0327]

[Chemical 130]

[0328] 4- [5- (4-methylphenyl) -3- (trifluoromethyl)-1H-pyrazole-1-yl] -2-fluoro-benzenesulfonamide The title compound was described in Example 3 METHOD Used and obtained by replacing 1- (3-chloro-4-methylphenyl) -ethanone with 1- (4-chlorophenyl) -ethanone: mp 126-128 ° C.

[0329]

[Chemical 131]

ESHRMS m / z 400.0753 (calculated as M + H ⁺ , 400.0
742). Example 5

[0331]

[Chemical 132]

[0332] 4- [5- (4-chlorophenyl) -3-trifluoromethyl -1H- Pirazo 1-yl] -2-fluoro-benzenesulfonamide The title compound using the method described in Example 3, Obtained by replacing 1- (3-chloro-4-methylphenyl) -ethanone with 1- (4-chlorophenyl) -ethanone and ethyl difluoroacetate with ethyl trifluoroacetate: m
p140-141 ° C.

[0333]

[Chemical 133]

ESHRMS m / z 420.0224 (calculated as M + H ⁺ , 420.0
197). Example 6

[0335]

[Chemical 134]

4- [5- (3-Fluoro-4-methoxy) -3-trifluoromethyl-1H- pyrazol-1-yl] -2-fluorobenzenesulfonamide The title compound was prepared by the method described in Example 3. Used by replacing 1- (3-chloro-4-methylphenyl) -ethanone with 1- (4-fluoro-3-methoxyphenyl) -ethanone and ethyl difluoroacetate with ethyl trifluoroacetate. : Mp124-126 ° C.

[0337]

[Chemical 135]

ESHRMS m / z 434.0598 (calculated as M + H ⁺ , 434.0.
617). Example 7

[0339]

[Chemical 136]

[0340] 2-fluoro-4- [5- (4-methoxyphenyl) -3- (trifluoromethyl Le)-1H-pyrazol-1-yl] benzenesulfonamide The title compound was described in Example 3 METHOD Used, replacing 1- (3-chloro-4-methylphenyl) -ethanone with 1- (4-methoxyphenyl) -ethanone and ethyl difluoroacetate with ethyl trifluoroacetate:
mp 130-131 ° C.

[0341]

[Chemical 137]

ESHRMS m / z 416.0692 (calculated as M + H ⁺ , 416.0.
680). Elemental analysis, calculated as C ₁₇ H ₁₃ F ₄ N ₃ O ₃ S: C, 49.16; H
, 3.15; N, 10.12; Found: C, 49.20; H, 3.01; N, 9
． 75. Example 8

[0343]

[Chemical 138]

[0344] 2-fluoro-4- [5- (4-fluorophenyl) -3- (trifluoromethyl Le)-1H-pyrazol-1-yl] benzenesulfonamide The title compound was described in Example 3 METHOD Used by replacing 1- (3-chloro-4-methylphenyl) -ethanone with 1- (4-fluorophenyl) -ethanone and ethyl difluoroacetate with ethyl trifluoroacetate:
mp 127-130 ° C.

[0345]

[Chemical 139]

ESHRMS m / z 404.0497 (calculated as M + H ⁺ , 404.0.
492). Elemental analysis, calculated as C ₁₆ H ₁₀ F ₅ N ₃ O ₂ S: C, 47.65; H
, 2.50; N, 10.42; Found: C, 47.43; H, 2.37; N, 1
0.24. Example 9

[0347]

[Chemical 140]

[0348] 2-fluoro-4- [5- (2-methoxyphenyl) -3- (trifluoromethyl Le)-1H-pyrazol-1-yl] benzenesulfonamide The title compound was described in Example 3 METHOD Used by replacing 1- (3-chloro-4-methylphenyl) -ethanone with 1- (2-methoxyphenyl) -ethanone and ethyl difluoroacetate with ethyl trifluoroacetate:
mp 159-160 ° C.

[0349]

[Chemical 141]

ESHRMS m / z 416.0675 (calculated as M + H ⁺ , 416.0.
692). Elemental analysis, calculated as C ₁₇ H ₁₃ F ₄ N ₃ O ₃ S: C, 49.16; H
, 3.15; N, 10.12; Found: C, 49.10; H, 3.12; N, 1
0.09. Example 10

[0351]

[Chemical 142]

4- [3- (difluoromethyl) -5- (3-fluoro-4-methoxyphenyl ) -1H-pyrazol-1-yl] -2-fluorobenzenesulfonamide The title compound is 1- (3-chloro -4-Methylphenyl) -ethanone was added to 1- (4
Obtained by substituting -fluoro-3-methoxyphenyl) -ethanone:
mp167-169 ° C.

[0353]

[Chemical 143]

ESHRMS m / z 416.0721 (calculated as M + H ⁺ , 416.0.
692). Elemental analysis, calculated as C ₁₇ H ₁₃ F ₄ N ₃ O ₃ S: C, 49.16; H
, 3.15; N, 10.12; Found: C, 49.20; H, 3.24; N, 9
． 95. Example 11

[0355]

[Chemical 144]

[0356] 5- [3-fluoro-4- (methylsulfonyl) phenyl] -1- (4-fluoride Rofeniru) -3- (trifluoromethyl)-1H-pyrazole

[0357]

[Chemical 145]

[0358] Step 1: 1- [3-fluoro-4- (methylthio) - phenyl] - manufacturing 3 ethanone ', 4'-difluoro acetophenone (100 g, 640 mmol) was dissolved in acetonitrile (700 mL). Sodium thiomethoxide was gradually added to the mixture while maintaining the temperature at -30 ° C. The reaction solution was stirred at room temperature overnight. The solid was removed by suction filtration and recrystallized from ethyl acetate and hexane to give a white crystalline solid, 1- [3-fluoro-4- (methylthio) -phenyl].
-Ethanone (90.5 g, 494 mmol, 77% yield): mp 72-78 ° C.

[0359]

[Chemical 146]

ESHRMS m / z 185.0412 (calculated as M + H ⁺ , 184.0
436). Elemental analysis, calculated for C ₉ H ₉ FOS: C, 58.67; H, 4.9
2; Found: C, 58.76; H, 4.85.

[0361]

[Chemical 147]

Step 2: Preparation of 4,4,4-trifluoro-1- [3-fluoro-4- (methylthio) phenyl] -1,3-butanedione 1- [3-fluoro-4- (methylthio)- Phenyl] -ethanone (41.5
0 g, 225 mmol) and ethyl trifluoroacetate were added to diethyl ether (1
000 mL). The reaction was stirred at room temperature for 1 hour and aqueous hydrochloric acid was added to adjust pH <1.0. The organic layer was separated, extracted with water (2X250mL), saturated ammonium chloride (2X250mL) and dried over sodium sulfate. The solvent was removed under vacuum and 4,4,4-trifluoro-1- [3-fluoro-4- (methylthio) phenyl] -1,3-butanedione was recrystallized from ethyl acetate and hexane (48.00 g. , 172 mmol, yield 76%): mp 66-68 ° C.
.

[0363]

[Chemical 148]

Elemental analysis, calculated for C ₉ H ₉ FOS: C, 47.14; H, 2.88; Found: C, 47.50; H, 2.71.

[0365]

[Chemical 149]

[0366] Step 3: 5- [3-fluoro-4- (methylthio) phenyl] -1- (4-full Orofeniru) -3- (trifluoromethyl)-1H-pyrazole manufacturing 4,4,4- Fluoro-1- [3-fluoro-4- (methylthio) phenyl] -1,3-butanedione (0.77 g, 2.8 mmol) was added to ethanol (2
0 mL) and concentrated hydrochloric acid was added to adjust pH <1.0. 4-Fluorophenylhydrazine hydrochloride (0.48g, 2.8mmol) was added and the mixture heated to reflux. After 1 hour, the solvent was removed under vacuum and the solid was washed with ethyl acetate (50 m
L). The solution is water (2X50 mL), saturated ammonium chloride (2X50 mL).
mL), dried over sodium sulfate and the solvent removed under vacuum. The obtained yellow oil, 5- [3-fluoro-4- (methylthio) phenyl] -1- (4-
Fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole was used without further purification.

[0367]

[Chemical 150]

ESHRMS m / z 371.0620 (calculated as M + H ⁺ , 371.0
641).

[0369]

[Chemical 151]

Step 4: Preparation of 5- [3-Fluoro-4- (methylsulfonyl) phenyl] -1- (4 -fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole 5- [3-Fluoro -4- (Methylthio) phenyl] -1- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole (1.00 g, 2.
75 mmol) and monoperoxyphthalic acid, magnesium salt hexahydrate (2.
30 g, 4.69 mmol) was added to methylene chloride: methanol (3: 1, 20 mL).
Mixed in. The mixture was stirred overnight at room temperature. The solid was suction filtered, the solvent removed under vacuum and the resulting slurry was dissolved in ethyl acetate (20 mL). The solution was extracted with water (2X25 mL), saturated ammonium chloride (2X25 mL), dried over sodium sulfate and the solvent removed under vacuum. Recrystallization from ethyl acetate and hexane gave 5- [3-fluoro-4- (methylsulfonyl) phenyl] -1- (
4-Fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole was obtained (0.66 g, 1.64 mmol, 60% yield): mp 228-229 ° C.
.

[0371]

[Chemical 152]

ESHRMS m / z 402.0474 (calculated as M + H ⁺ , 402.0
461). Elemental analysis, calculated as C ₁₇ H ₁₁ F ₅ O ₂ S: C, 50.75; H, 2
． 76; N, 6.96; Found: C, 50.63; H, 2.57; N, 6.76.
. Example 12

[0373]

[Chemical 153]

1-Cyclohexyl-5- [3-fluoro-4- (methylsulfonyl) phenyl ] -3- (trifluoromethyl) -1H-pyrazole The title compound uses the method described in Example 11 and 4- Obtained by substituting fluorophenylhydrazine for cyclohexylhydrazine: mp228-
229 ° C.

[0375]

[Chemical 154]

[0376] ESHRMS m / z 390.1022 (calculated as M, 390.1025
). Elemental analysis, C₁₇H₁₈F_FourN₂O₂Calculated as S: C, 52.30; H, 4,
65; N, 7.18; Found: C, 52.47; H, 4.51; N, 7.11. Example 13

[0377]

[Chemical 155]

[0378] 5- [3-fluoro-4- (methylsulfonyl) phenyl] -3- (a trifluoromethyl) -1- [3- (trifluoromethyl) phenyl)] - 1H-Pirazo le The title compound is prepared analogously to Example 11 Obtained by substituting 3-trifluoromethylphenylhydrazine for 4-fluorophenylhydrazine using the method described in mp 162-168 ° C.

[0379]

[Chemical 156]

[0380] ESHRMS m / z 452.0418 (calculated as M, 452.0429
). Elemental analysis, C₁₈H₁₁F₇N₂O₂Calculated as S: C, 47.79; H, 2.
45; N, 6.19; Found: C, 47.87; H, 2.31; N, 6.12. Example 14

[0380]

[Chemical 157]

[0382] 5- [3-fluoro-4- (methylsulfonyl) phenyl] -3- (a trifluoromethyl) -1- [4- (trifluoromethoxy) phenyl)] - 1H-pyrazole Lumpur The title compound is prepared analogously to Example Obtained by substituting 4-trifluoromethoxyphenylhydrazine for 4-fluorophenylhydrazine using the method described in 11 .: mp 110-112 ° C.

[0383]

[Chemical 158]

[0384] ESHRMS m / z 468.0338 (calculated as M, 468.0379
). Elemental analysis, C₁₈H₁₁F₇N₂O₃Calculated as S: C, 46.16; H, 2.
37; N, 5.98; Found: C, 46.22; H, 2.49; N, 5.91. Example 15

[0385]

[Chemical 159]

1- (3-Chloro-4-methylphenyl) -5- [3-fluoro-4- ( methylsulfonyl) phenyl] -3- (trifluoromethyl) -1H-pyrazole The title compound was obtained in Example 11. Obtained by replacing 4-fluorophenylhydrazine with 3-chloro-4-methylphenylhydrazine using the method described: mp 144-145 ° C.

[0387]

[Chemical 160]

ESHRMS m / z 433.0395 (calculated as M + H ⁺ , 433.0
401). Elemental _{analysis, C 18 H 13 ClF 4 N} 2 O 2 S Calculated: C, 49.95
H, 3.03; N, 6.47; Found: C, 49.90; H, 2.84; N,
6.29. Example 16

[0389]

[Chemical 161]

4- [5- [3-Fluoro-4- (methylsulfonyl) phenyl] -3- ( trifluoromethyl) -1H-pyrazol-1-yl] benzonitrile The title compound was the method described in Example 11. Obtained by substituting 4-cyanophenylhydrazine for 4-fluorophenylhydrazine: mp15
2-153 ° C.

[0391]

[Chemical 162]

ESHRMS m / z 427.0830 (calculated as M + NH ₄ ⁺ , 427.
0852). Elemental _{analysis, C 18 H 11 F 4 N} 3 O 2 S Calculated: C, 52.81;
H, 2.71; N, 10.26; Found: C, 52.49; H, 2.43; N,
9.87. Example 17

[0393]

[Chemical formula 163]

5- [3-Fluoro-4- (methylsulfonyl) phenyl] -1- (3- methylphenyl) -3- (trifluoromethyl) -1H-pyrazole The title compound was prepared by the method described in Example 11. Used and obtained by replacing 4-fluorophenylhydrazine with 3-methylphenylhydrazine: mp12
9-130 ° C.

[0395]

[Chemical 164]

ESHRMS m / z 399.0838 (calculated as M + H ⁺ , 399.0.
790). Elemental analysis, calculated as C ₁₈ H ₁₄ F ₄ N ₃ O ₂ S: C, 54.27; H
, 3.54; N, 7.03; Found: C, 54.11; H, 3.36; N, 7.
23. Example 18

[0397]

[Chemical 165]

[0398] 3- how (difluoromethyl) -5- [3-fluoro-4- (methylsulfonyl) off Eniru] -1- (4-fluorophenyl)-1H-pyrazole The title compound described in Example 11 Used and obtained by replacing ethyl trifluoroacetate with ethyl difluoroacetate: mp 201-202 ° C.

[0399]

[Chemical 166]

ESHRMS m / z 385.0643 (calculated as M + H ⁺ , 385.0
634). Elemental analysis, 3.15; N, 7.29; Found: C, 53.01; H,
3.01; N, 7.23. Example 19

[0401]

[Chemical 167]

1-Cyclohexyl-3- (difluoromethyl) -5- [3-fluoro-4- ( methylsulfonyl) phenyl] -1H-pyrazole The title compound uses the method described in Example 11 and 4-fluoro Obtained by replacing phenylhydrazine with cyclohexylhydrazine and ethyl trifluoroacetate with ethyl difluoroacetate: mp 138-139 ° C.

[0403]

[Chemical 168]

ESHRMS m / z 373.1203 (calculated as M + H ⁺ , 373.1
198). Elemental _{analysis, C 17 H 19 F 3 N} 2 O 2 S Calculated: C, 54.83; H
, 5:14; N, 7.52; Found: C, 54.84; H, 5.06; N, 7,
59. Example 20

[0405]

[Chemical 169]

1- (3-Chloro-4-methylphenyl) -3- (difluoromethyl) -5- [ 3-fluoro-4- (methylsulfonyl) phenyl] -1H-pyrazole The title compound is described in Example 11. Obtained by replacing 4-fluorophenylhydrazine with 3-chloro-4-methylphenylhydrazine and ethyl trifluoroacetate with ethyl difluoroacetate using the method described above: mp146-1.
47 ° C.

[0407]

[Chemical 170]

ESHRMS m / z 415.0494 (calculated as M + H ⁺ , 415.0
495). Elemental _{analysis, C 18 H 14 ClF 3 N} 2 O 2 S Calculated: C, 52.12
H, 3.40; N, 6.75; Found: C, 52.04; H, 3.29; N,
6. 75. Example 21

[0409]

[Chemical 171]

[0410] 3- (difluoromethyl) -5- [3-fluoro-4- (methylsulfonyl) off Eniru] -1- [3- (trifluoromethyl) phenyl]-1H-pyrazole The title compound in Example 11 Obtained using the method described by replacing 4-fluorophenylhydrazine with 3-trifluoromethylphenylhydrazine and ethyl trifluoroacetate with ethyl difluoroacetate: mp110-1.
11 ° C.

[0411]

[Chemical 172]

ESHRMS m / z 435.0599 (calculated as M + H ⁺ , 435.0
602). Elemental _{analysis, C 18 H 12 F 6 N} 2 O 2 S Calculated: C, 49.77; H
, 2.78; N, 6.45; Found: C, 49.77; H, 2.68; N, 6.
30. Example 22

[0413]

[Chemical 173]

[0414] 2-fluoro-4- [3- (4-fluorophenyl) -5-methyl-4- Isoo Kisazoriru] - benzenesulfonamide

[0415]

[Chemical 174]

[0416] Step 1: 4-Fluoro-.alpha. - [(trimethylsilyl) - oxy] Production of 4-fluorobenzaldehyde of benzene acetonitrile (21.0 g, 170 mmol) and zinc iodide with (30 mg) together in methylene chloride Mixed. The solution was cooled to -70 ° C and trimethylsilyl cyanide (16.8 g, 170 mmol) was added slowly.
The cooling bath was removed and the solution was stirred for 1 hour while warming to room temperature. The solution is water (2
X100 mL), saturated ammonium chloride (2X100 mL), and dried over sodium sulfate. The solvent was removed under vacuum to give 4-fluoro-α-[(trimethylsilyl) -oxy] benzeneacetonitrile as a yellow oil (23.
0 g, 95.8 mmol, yield 61%):

[0417]

[Chemical 175]

ESHRMS m / z 241.1172 (calculated as M + NH ₄ ⁺ , 241.
1172).

[0419]

[Chemical 176]

[0420] Step 2: 2- (3-fluorophenyl) -1- (4-fluorophenyl) ethanol down the production of 4-fluoro-.alpha. - [(trimethylsilyl) - oxy] benzene - acetonitrile (23.0 g, 104 mmol A solution of () in tetrahydrofuran (300 mL) was cooled to -78 ° C. A 1.0 M solution of lithium diisopropylamide in tetrahydrofuran (115 mL, 115 mmol) was added dropwise over 1 hour. The solution was stirred at -78 ° C for 1 hour. 3-fluorobenzyl bromide (19.6 g,
104 mmol) as a tetrahydrofuran (100 mL) solution was added over 25 minutes. The solution was kept at -78 ° C for 1 hour and then warmed to 0 ° C over 2 hours. Aqueous hydrochloric acid solution (10% X 200 mL) was added, and the solution was stirred at room temperature for 24 hours.
The layers were separated and the organic layer was mixed with 15% aqueous sodium hydroxide solution (100 mL),
Stir at room temperature for 24 hours. Collect the organic layers and add saturated ammonium chloride (200 mL).
It was washed with and dried over sodium sulfate. The solvent was removed under vacuum to give a yellow oil. 2- (3-Fluorophenyl) -1- (4-fluorophenyl) ethanone was isolated by preparative silica chromatography, followed by crystallization from ethyl acetate and hexane. (Yield 42%): mp 47-48 ° C.

[0421]

[Chemical 177]

ESHRMS m / z 233.0791 (calculated as M + H ⁺ , 233.0
778). Elemental analysis, calculated for C ₁₄ H ₁₁ F ₂ O: C, 72.41; H, 4.
34; found: C, 72.32; H, 4.30.

[0423]

[Chemical 178]

[0424] Step 3: 2- (3-fluorophenyl) -1- (4-fluorophenyl) ethanol emissions oxime of 2- (3-fluorophenyl) -1- (4-fluorophenyl) ethanone (8
． 82 g, 38 mmol), hydroxylamine hydrochloride (5.55 g, 38 mmol) and ammonium acetate (6.50 g, 38 mmol) in ethanol (1
Reflux in 50 mL) and water (50 mL). Remove the ethanol under vacuum,
The aqueous suspension was poured into ethyl acetate (200 mL), extracted with water (2X200 mL), saturated ammonium chloride (2X250 mL) and dried over sodium sulfate. The solvent was removed under vacuum and 2- (3-fluorophenyl) -1- (4-fluorophenyl) ethanone oxime (6.19 g, 25.0 mmol) was obtained by crystallization from boiling hexane (yield). 65%): mp 60-67 ° C.

[0425]

[Chemical 179]

ESHRMS m / z 248.0899 (calculated as M + H ⁺ , 248.0
887). Elemental analysis, calculated as C ₁₄ H ₁₁ F ₂ NO: C, 68.01; H, 4
． 48; N, 5.67; Found: C, 67.86; H, 4.44; N, 5.63.
.

[0427]

[Chemical 180]

Step 4: Preparation of 4- (3-fluorophenyl) -3- (4-fluoro-phenyl-4,5 -dihydro-5-methyl-5-isoxazole (mixture of diastereomers ) 2- ( 3-Fluorophenyl) -1- (4-fluorophenyl) ethanone Oxime (7.39 g, 30 mmol) was dissolved in tetrahydrofuran (500 mL) and cooled to -78 ° C. 2.5 M n-butyllithium (50 mL). Was added over 1 hour and maintained at -78 ° C for an additional hour. Acetylimidazole (
6.51 g, 60 mmol) was added and the suspension was warmed to room temperature. PH of solution <1
． To adjust to 0, a 10% hydrochloric acid aqueous solution was added. The solution is water (2X250 mL),
It was extracted with ammonium chloride (2X250 mL) and dried over sodium sulfate. Four
A mixture of-(3-fluorophenyl) -3- (4-fluoro-phenyl-4,5-dihydro-5-methyl-5-isoxazole diastereomers was purified by preparative silica chromatography followed by ethyl acetate and Isolated by crystallization from hexane (4.07 g, 14.08 mmol, 47% yield): mp130.
-132 ° C.

[0429]

[Chemical 181]

ESHRMS m / z 290.0993 (calculated as M + H ⁺ , 290.0
993). Elemental _{analysis, C 16 H 13 F 2 NO} 2 Calculated: C, 66.43; H, 4
． 53; N, 4.84; Found: C, 66.48; H, 4.54; N, 4.76.
.

[0431]

[Chemical 182]

Step 5: 2-Fluoro-4- [3- (4-fluorophenyl) -5-methyl-4 -isoxazolyl] benzenesulfonamide Chlorosulfonic acid (8.0 mL) was cooled to 0 ° C. and 4- ( 3-Fluorophenyl) -3- (4-fluoro-phenyl-4,5-dihydro-5-methyl-5-isoxazole (0.53 g, 18 mmol) was added.After stirring at 0 ° C. for 1 hour,
The solution was added dropwise on ice (200 mL) with vigorous stirring. The solution is ethyl acetate (
2X100 mL). Merged the ethyl acetate layer, water (2X100mL),
Extracted with saturated ammonium chloride (2 × 100 mL). Ammonium hydroxide (50 mL) was added to the ethyl acetate solution and the mixture was stirred at room temperature overnight. Saturated ammonium chloride (50 mL) was added, the ethyl acetate layer was separated, and saturated ammonium chloride (
2 × 100 mL) and dried over sodium sulfate. 2-fluoro-4- [
3- (4-Fluorophenyl) -5-methyl-4-isoxazolyl] benzenesulfonamide (0.10 g, 0.28 mmol) was purified by preparative silica chromatography followed by crystallization from ethyl acetate and hexane. Obtained (0.
10 g, 15% yield: mp176-177 degreeC.

[0433]

[Chemical 183]

ESHRMS m / z 351.0598 (calculated as M + H ⁺ , 351.0
615). Elemental analysis, calculated as C ₁₆ H ₁₂ F ₂ N ₂ O ₃ S: C, 54.85; H
, 3.45; N, 8.00; Found: C, 54.99; H, 3.33; N, 7.
82. Example 23

[0435]

[Chemical 184]

[0436] 2- Furuoro 4- [3- (4-fluorophenyl) -5-methyl-4- Isoo Kisazoriru] benzenesulfonamide The title compound, using the method described in Example 22, 4-fluorobenzaldehyde Was obtained by substituting benzaldehyde for: mp 180-182
° C.

[0437]

[Chemical 185]

ESHRMS m / z 333.0727 (calculated as M + H ⁺ , 333.0
709). Elemental analysis, calculated for C ₁₆ H ₁₃ FN ₂ O ₃ S: C, 57.82; H,
3.94; N, 8.43; Found: C, 57.43; H, 4.00; N, 8.3.
1. Example 24

[0439]

[Chemical 186]

4- [3-Fluoro-4- (methylsulfonyl) phenyl] -3-phenyl-2 (5H) -furanone

[0441]

[Chemical 187]

[0442] Step 1: 2-bromo-1- [3-fluoro-4- (methylthio) phenyl] ethanone of preparation of 1- [3-fluoro-4- (methylthio) phenyl] ethanone (10.30 g
, 56.0 mmol) with glacial acetic acid (50 mL) and hydrogen bromide (20 mL, 35%).
Suspended in acetic acid solution). Bromine (8.95 g, 56 mmol) was added and the reaction was stirred at room temperature for 30 minutes. Ethyl acetate (50 mL) was added to the reaction solution, and water (2X50 m
L), extracted with saturated ammonium chloride (2 × 50 mL) and dried over sodium sulfate. The solvent was removed under vacuum to give 2-bromo-1- [3-fluoro-4- (methylthio) phenyl] ethanone as a yellow solid (10.45 g, 3).
9.8 mmol, 71% yield): mp 70-71 ° C.

[0443]

[Chemical 188]

ESHRMS m / z 262.9544 (calculated as M + H ⁺ , 262.9
542). Elemental analysis, calculated as C ₉ H ₈ FBrOS: C, 41.08; H, 3
． 06; Found: C, 41.00; H, 2.88.

[0445]

[Chemical 189]

Step 2: Preparation of 4- [3-fluoro-4- (methylthio) -phenyl] -3-phenyl- 2 (5H) -furanone Phenylacetic acid (3.61 g, 26.5 mmol) and sodium hydroxide. (2
． 6 g, 50% aqueous solution) was dissolved in dimethylformamide and stirred vigorously for 15 minutes. 2-Bromo-1- [3-fluoro-4- (methylthio) phenyl] ethanone (5.17 g, 19.6 mmol) was added and the reaction was warmed to 45 ° C. for 1 hour.
Ethyl acetate (50 mL) was added to the reaction solution, and the organic layer was mixed with 10% hydrochloric acid aqueous solution (2X50
mL), water (2X50 mL), saturated ammonium chloride (2X50 mL) and dried over sodium sulfate. The solvent was removed under vacuum to give a yellow solid.
The solid was dissolved in methylene chloride and concentrated sulfuric acid (1 mL) was added. After 15 minutes, the solution was extracted with water (2X50 mL), saturated ammonium chloride (2X50 mL) and dried over sodium sulfate. The solvent was removed under vacuum and 4- [3-fluoro-4- (methylthio) -phenyl] -3-phenyl-2 (5H) -furanone (1.85 g, 6
． 16 mmol) was obtained by crystallization from ethyl acetate (yield 31%):
mp 159-160 ° C.

[0447]

[Chemical 190]

ESHRMS m / z 301.0680 (calculated as M + H ⁺ , 301.0
699). Elemental analysis, calculated for C ₁₇ H ₁₃ FO ₂ S: C, 67.98; H, 4
． 36; Found: C, 67.55; H, 4.10.

[0449]

[Chemical 191]

[0450] Step 3: 4- [3-fluoro-4- (methylsulfonyl) - phenyl] -3-off Eniru -2 (5H) - furanone manufacturing 4- [3-fluoro-4- (methylthio) - phenyl ] -3-Phenyl-2 (
5H) -furanone (1.80 g, 6.00 mmol) and monoperoxyphthalic acid, magnesium salt hexahydrate (3.70 g, 6.00 mmol) in methylene chloride: methanol (3: 1, 40 mL). Mixed. The mixture was stirred overnight at room temperature. The solid was filtered off with suction and discarded, the solvent was removed under vacuum and the resulting slurry was dissolved in ethyl acetate (20 mL). The solution was extracted with water (2X25 mL), saturated ammonium chloride (2X25 mL), dried over sodium sulfate and the solvent removed under vacuum. Crystallization from ethyl acetate and hexane gave 4- [3-fluoro-4- (methylsulfonyl) -phenyl] -3-phenyl-2 (5H) -furanone (0.63 g, 1.89 mmol, yield). 32%): mp161-1
62 ° C.

[0451]

[Chemical 192]

ESHRMS m / z 333.0606 (calculated as M + H ⁺ , 333,0)
597). Elemental analysis, calculated for C ₁₇ H ₁₃ FO ₄ S: C, 61.44; H, 3
． 94; Found: C, 61.65; H, 3, 93.

Biological Evaluation In Vitro Evaluation of COX-1 and COX-2 Activity The compounds of the present invention exhibit in vitro inhibition of COX-2. The COX-2 inhibitory activity of the compounds of the present invention exemplified in the examples was determined by the following method.

A. Preparation of Recombinant COX Baculovirus Recombinant COX-1 and COX-2 are described in Gierse et al, [J.
Biochem. , 305, 479-84 (1995)]. D. R. O'Reilly et al (Baculovi
rus Expression Vectors: A Laboratory
Human or mouse COX- in a manner similar to that of Manual (1992)).
One or a 2.0 kb fragment containing the coding region of human or mouse COX-2 was added to the baculovirus transfer vector pVL1393 (Invitrogen).
Was cloned into the BamHI site of E. coli to generate baculovirus transfer vectors for COX-1 and COX-2. Recombinant baculovirus was isolated by the calcium phosphate method by transfecting 4 μg of baculovirus transfer vector into SF9 insect cells (2 × 10 ⁸ ) with 200 ng of linearized baculovirus plasmid DNA. M. D. Summers
and G.D. E. Smith, A Manual of Methods fo
r Baculovirus Vectors and Insect Cel
l Culture Procedures, Texas Agric. Exp
． Station Bull. 1555 (1987). Recombinant baculovirus was purified by three rounds of plaque purification and yielded high virus titers (1
(0 ⁷ -10 ⁸ pfu / mL) stock was prepared. For large scale production, SF9 insect cells were infected with recombinant baculovirus stocks (0.5 × 10 ⁶ / mL) in a 10 liter fermentor to a multiplicity of infection of 0.1. After 72 hours, the cells were centrifuged and the cell pellet was washed with tris / sucrose (50 mM: 25) containing 1% 3-[(3-colamidopropyl) dimethylammonio] -1-propanesulfonate (CHAPS). %, PH 8.0). The homogenate was centrifuged at 10,000 xG for 30 minutes and the resulting supernatant stored at -80 ° C until assayed for COX activity.

B. COX-1 and COX-2 activity assays COX activity using an ELISA to detect the prostaglandin released was assayed as PGE ₂ / [mu] g protein / time is formed. Potassium phosphate buffer (50 mM containing epinephrine, phenol and heme
, PH 8.0) and arachidonic acid (10 μM) was added to incubate CHAPS solubilized insect cell membranes containing the appropriate COX enzyme. Compounds and enzymes were pre-incubated for 10-20 minutes prior to arachidonic acid addition.
The reaction of arachidonic acid with the enzyme was stopped after 10 minutes at 37 ° C./room temperature by transferring 40 μl of the reaction mixture to 160 μl of ELISA buffer and 25 μM indomethacin. The PGE ₂ formed is standard ELISA technology (Cayman Ch
electrical). The results are shown in Table I.

[0456]

[Table 1]

C. Rapid Assay for COX-1 and COX-2 Activity COX activity was assayed as PGE ₂ / μg protein / hour formed using an ELISA to detect released prostaglandins. Potassium phosphate buffer (0.05M potassium phosphate, pH 7.5, 2 μM phenol,
20 μl of 100 μM arachidonic acid in 1 μM heme, 300 μM epinephrine)
(10 μM) was added to incubate CHAPS-solubilized insect cell membranes containing the appropriate COX enzyme. Prior to the addition of arachidonic acid, 2 compounds and enzymes were added.
Pre-incubated for 10 minutes at 5 ° C. The reaction between arachidonic acid and the enzyme is
After 2 minutes at 37 ° C./room temperature, 40 μl of the reaction mixture was stopped by transferring to 160 μl of ELISA buffer and 25 μM indomethacin. The PGE ₂ formed was measured by standard ELISA technique (Cayman Chemical).
The results are shown in Table II.

[0458]

[Table 2]

Rat Carrageenan Paw Toe Edema Test The Carrageenan Paw Edema Test was performed in accordance with Winter, et al. , (Proc. Soc
． Exp. Biol. Med. , 111, 544 (1962)), with materials, reagents and methods essentially as described. Male Sprague-Dawley rats are selected in each group so that the average body weight is as close as possible. Rats are fasted with water ad libitum for at least 16 hours prior to testing. Rats are orally dosed with the compound suspended in a carrier containing 0.5% methylcellulose and 0.025 surfactant, or the carrier alone (
1 mL). One hour later, 0.1 mL of carrageenan / sterilized 0.9% saline 1% solution was injected subplantar, and the volume of the injected foot was measured by a moving volume fluctuation recorder connected to a digital pressure transducer. To do. The volume of the paw is measured again 3 hours after the injection of carrageenan. Mean paw swelling in the drug-treated animal group is compared to that of the placebo-treated animal group to determine the percentage inhibition of edema (Otterness and B.
liven, Laboratory Models for Testing
NSAIDs, Non-stereodal Anti-Inflammato
ry Drugs, (J. Lombardino, eds., 1985)).

Rat Carrageenan-Induced Analgesia Test The rat carrageenan-induced analgesia test was performed by Hargreaves, et al. 、 (
Pain, 32, 77 (1988)) performed with materials, reagents and methods essentially as described. Male Sprague-Dawley rats are treated as previously described in the carrageenan toes edema test. Carrageenan injection 3
After hours, place the rat in a special plexiglass container with a transparent floor that can be placed under the floor and has a high intensity lamp as a radiant heat source. After the first 20 minutes, begin to give heat stimulus to the injected or contralateral uninjected paw. A photocell stops the lamp and timer when light is blocked by foot retraction. The time until the rat withdraws its paw is measured. Withdrawal refractory time is determined in seconds for control and drug treated groups to determine percent inhibition of hyperalgesic paw withdrawal.

While various changes can be made in the above methods and devices without departing from the scope of the invention, all things contained in the above description are intended to be interpreted as illustrative and not in a limiting sense. Has been done. All documents mentioned in this application are
All are specifically incorporated by reference as if set forth in full.

All cited references are incorporated by reference as if written here. When referring to elements of the invention or preferred embodiments thereof, the article "a"
“A”, “an”, “the” and “said” are intended to mean that one or more elements are present. The terms “consisting of”, “including” and “Have” is intended to be inclusive and means that there may be additional elements other than the listed elements.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/42 A61K 31/42 4H006 31/44 31/44 A61P 19/02 A61P 19/02 29/00 29 / 00 35/00 35/00 43/00 111 43/00 111 123 123 C07D 213/61 C07D 213/61 231/12 231/12 C 261/08 261/08 307/58 307/58 333/18 333 / 18 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA ( BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH , CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO , RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Radwig, Cindy El 1412 Daughter Lane, Sent Lewis, 63146, Missouri, United States (72) Inventor Tarry, John Jay 63109, Missouri, United States, Sent Lewis, Clifton Court 4701 F-term (reference) 4C037 JA02 4C055 AA01 BA02 BA06 BB02 CA03 CA20 CA39 CB03 DA01 4C056 AA01 AB01 AC01 AD01 AE03 AF01 4C086 AA01 AA02 AA03 BA03 BB02 BC17 BC67 MA01 MA04 MA35 MA37 MA52 MA56 MA66 NA14 NA15 ZA96 ZB11 ZB26 ZC20 4C206 AA01 AA03 JA19 MA01 MA04 MA37 MA55 MA72 MA76 MA86 NA14 NA15 ZA96 ZB11 ZB26 ZC20 4H006 AA01 TAA02 AB22 AB22 AB02 AB22

Claims (113)

[Claims] 1. Formula I: [Wherein ^A is a 5- or 6-membered ring substituent selected from partially saturated or unsaturated heterocyclic and carbocyclic rings; R ¹ is cyclohexyl, pyridinyl or phenyl; Wherein cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl,
Cyano, carboxyl, C _1-2 -alkoxycarbonyl, hydroxyl, C _1-2-
Hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl, C _1-2 -alkylsulfinyl, halo, It may be substituted with 1, 2 or 3 groups selected from C _1-2 -alkoxy and C _1-3 -alkylthio; R ² is methyl or amino; R ³ is hydride, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 - alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 - haloalkyl, heterocyclyl, cycloalkenyl, phenyl -C _1-3 - alkyl, heterocyclyl -C _1-3 - Alkyl, C _1-3 - alkylthio -C _1-3 - alkyl, C _1-3 - hydroxyalkyl,
C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3 -alkyl, phenylthio-C _1-3 -Alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _{1- 3} -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkylamino, N-arylamino, N - aralkylamino, N- (C _1-3 - alkyl) -N- aralkylamino, N- (C _{1 -3} - alkyl) - N-arylamino, amino-C _1-3 -alkyl, C _1-3 -alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-
C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-
C _1-3 -alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-
Phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl,
C _1-3 -alkylsulfonyl, aminosulfonyl, C _1-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3
Represents one or more groups selected from -alkyl) -N-phenylaminosulfonyl, provided that (a) A is not pyrrolyl and (b) A is not oxazolyl other than oxazolonyl; ^{When 1} is 4-bromophenyl: (a) R ² is methyl and R ³
Is hydrogen, cyano, trifluoromethyl or ethoxycarbonyl, A is not pyrazolyl; (b) when R ³ is trifluoromethyl, A is not imidazolyl; (c) R ³ is methyl In some cases, A is not isoxazolyl; (d) When R ³ is hydrogen, A is not 2-furanonyl; provided that R ¹ is 3-methyl-4-bromophenyl and R ² is methyl. And
When R ³ is trifluoromethyl, A is not imidazolyl. ] Or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 2. A is a 5- or 6-membered ring substituent selected from partially saturated or unsaturated heterocyclic and carbocyclic rings; R ¹ is cyclohexyl, pyridinyl or Phenyl, wherein cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl,
Cyano, carboxyl, C _1-2 -alkoxycarbonyl, hydroxyl, C _1-2-
Hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl, C _1-2 -alkylsulfinyl, halo, It may be substituted with 1, 2 or 3 groups selected from C _1-2 -alkoxy and C _1-3 -alkylthio; R ² is methyl or amino; R ³ is hydride Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, (5- or 6-membered heterocyclyl) Oxy, C _1-3 -alkoxy, C _1-3 -alkylthio, C _1-3 -alkylcarbonyl, C _3-6 -cycloalkyl, phenyl, C _1-3
-Haloalkyl, 5- or 6-membered ring heterocyclyl, C _3-6 -cycloalkenyl, phenyl-C _1-3 -alkyl, (5- or 6-membered ring heterocyclyl)
-C _1-3 -alkyl, C _1-3 -alkylthio-C _1-3 -alkyl, C _1-3 -hydroxyalkyl, C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-
C _1-3 - alkylcarbonyl, phenyl -C _2-3 - alkenyl, C _1-3 - alkoxy -C _1-3 - alkyl, phenylthio -C _1-3 - alkyl, phenyloxy -C _1-3 - alkyl, C _1-3 -alkoxyphenyl-C _1-3 -alkoxy-C _1-3 -alkyl, C _1-3 -alkoxycarbonyl-C _1-3 -alkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy- C _1-3 - alkyl, C _1-3 - alkylamino, N- phenylamino, N- (phenyl -
C _1-3 -alkyl) amino, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3
-Alkyl) amino, N- (C _1-3 -alkyl) -N-phenylamino, amino-C _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl, N-phenylamino- C _1-3 -alkyl, N-phenyl-C _1-3 -alkylamino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-phenyl-C _1-3 -alkylamino-C _1-3 - alkyl, N-(C _1-3 - alkyl) -N- phenylamino -C _1-3 - alkyl, phenyloxy, phenyl -C _1-3 - alkoxy, phenylthio, phenyl -C _1-3 - alkylthio, C _1-3 - alkylsulphinyl, C _1-3 - alkyl, aminosulfonyl, C _1-3 - alkyl aminosulfonyl, N- phenylamino, phenylsulfonyl and N-(C _1-3 - alkyl) - N
-A compound according to claim 1 which represents one or more groups selected from phenylaminosulfonyl; or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 3. The compound according to claim 2, wherein A is a 5- or 6-membered ring substituent selected from a partially saturated or unsaturated heterocyclic ring. 4. The compound according to claim 2, wherein A is a 5- or 6-membered ring substituent selected from partially saturated or unsaturated carbocyclic rings. 5. A is thienyl, furyl, furanone, thiazolyl, oxothiazolyl, thioxothiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, oxooxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, The compound according to claim 2, which is a group selected from benzindazolyl, benzopyranopyrazolyl, phenyl and pyridyl. 6. A is thienyl, furyl, furanone, thiazolyl, oxothiazolyl, thioxothiazolyl, imidazolyl, benzofuryl, indenyl, benzothienyl, isoxazolyl, pyrazolyl, cyclopentenyl, cyclopentadienyl, benzindazolyl, The compound according to claim 2, which is a group selected from benzopyranopyrazolyl, phenyl and pyridyl. 7. The compound according to claim 2, wherein A is a group selected from thienyl, furanone, isoxazolyl, pyrazolyl, cyclopentenyl and pyridinyl. 8. The compound according to claim 2, wherein A is a group selected from furanone, isoxazolyl and pyrazolyl. 9. The compound according to claim 6, wherein R ¹ is optionally substituted cyclohexyl. 10. The compound according to claim 6, wherein R ¹ is optionally substituted pyridinyl. 11. The method according to claim 6, wherein R ¹ is an optionally substituted phenyl.
The compound according to. 12. R ¹ is cyclohexyl, pyridinyl or phenyl, said cyclohexyl, pyridinyl and phenyl being methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, Amino, methylamino,
The compound according to claim 6, which may be substituted with one, two or three groups selected from phenylamino, nitro, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio. 13. R ³ is hydride, fluoro, chloro, bromo, methyl,
Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl, phenyloxymethyl, methoxyphenylmethoxymethyl,
Methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino, N-phenylamino, N- ( Phenylmethyl) amino, N-methyl-
N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N-phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N- Methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, methylsulfonyl, aminosulfonyl,
The compound according to claim 6, which is a group selected from methylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N-methyl-N-phenylaminosulfonyl. 14. R ¹ is cyclohexyl or phenyl, and said cyclohexyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino. , Phenylamino, nitro,
It may be substituted with one, two or three groups selected from methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio; R ³ is hydride, fluoro, chloro, bromo, methyl, Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl,
Phenyloxymethyl, methoxyphenylmethoxymethyl, methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino , N-phenylamino, N- (phenylmethyl) amino, N-methyl-N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N- Phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N-methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, Chirusuruhoniru, aminosulfonyl, methylaminosulfonyl, N- phenylamino, phenylsulfonyl and N- methyl -
The compound according to claim 6, which is a group selected from N-phenylaminosulfonyl. 15. R ¹ is cyclohexyl or phenyl, wherein said cyclohexyl and phenyl are halo, cyano, C _1-2 -alkyl, C _1-2 -haloalkyl, C _1-2 -alkoxy and C _1-2. One selected from haloalkoxy,
It may be substituted with 2 or 3 groups; R ³ is hydride, C _1-2 -alkyl, C _1-3 -alkoxy, C _1-3 -alkylcarbonyl, C _1-3 -haloalkyl, C 3. _1-3 - hydroxyalkyl and C _1-3 - is a group selected from alkoxycarbonyl, a compound according to claim 6. 16. R ¹ is cyclohexyl or phenyl, said cyclohexyl and phenyl being one selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro, bromo and methoxy, Optionally substituted with 2 or 3 groups; R ³ is a group selected from hydride, methyl, methoxy, methylcarbonyl, trifluoromethyl, difluoromethyl, hydroxymethyl and methoxycarbonyl. The compound according to. 17. Formula II: embedded image [In the formula, R ⁴ is cyclohexyl, pyridinyl or phenyl, and the cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl, cyano, carboxyl, C _1-2 -alkoxycarbonyl, Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl,
C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, two or may be substituted by three radicals; is R ^5, hydrido, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 -alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 -haloalkyl, heterocyclyl, cycloalkenyl, phenyl-C _1-3 -alkyl, heterocyclyl-C _1-3 -alkyl, C _1-3 -alkylthio-C _1-3 -alkyl, C _1-3 -hydroxyalkyl,
C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3 -alkyl, phenylthio-C _1-3 -Alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _{1- 3} -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkylamino, N-arylamino, N - aralkylamino, N- (C _1-3 - alkyl) -N- aralkylamino, N- (C _{1 -3} - alkyl) - N-arylamino, amino-C _1-3 -alkyl, C _1-3 -alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-
C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-
C _1-3 -alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-
Phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl,
C _1-3 -alkylsulfonyl, aminosulfonyl, C _1-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3
- alkyl) -N- be a group selected from phenyl aminosulfonyl; when R ⁶ is a methyl or amino, provided that, R ⁴ is 4-bromophenyl, R ⁶ is methyl, R ⁵ Is not hydrogen, cyano, trifluoromethyl or ethoxycarbonyl. ] The compound of Claim 1 which has these; or its pharmaceutically acceptable salt, a tautomer, or a prodrug. 18. R ⁴ is cyclohexyl, pyridinyl, or phenyl, wherein cyclohexyl, pyridinyl and phenyl, C _1-2 - alkyl, C _{1 -2} - haloalkyl, cyano, carboxyl, C _1-2 - alkoxycarbonyl , Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2-.
Alkyl, C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ⁵ is, Hydride, halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, (5- or 6-membered ring heterocyclyl). R) oxy, C _1-3 -alkoxy, C _1-3 -alkylthio, C _1-3 -alkylcarbonyl, C _3-6 -cycloalkyl, phenyl, C _1-3
-Haloalkyl, 5- or 6-membered ring heterocyclyl, C _3-6 -cycloalkenyl, phenyl-C _1-3 -alkyl, (5- or 6-membered ring heterocyclyl)
-C _1-3 -alkyl, C _1-3 -alkylthio-C _1-3 -alkyl, C _1-3 -hydroxyalkyl, C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-
C _1-3 - alkylcarbonyl, phenyl -C _2-3 - alkenyl, C _1-3 - alkoxy -C _1-3 - alkyl, phenylthio -C _1-3 - alkyl, phenyloxy -C _1-3 - alkyl, C _1-3 -alkoxyphenyl-C _1-3 -alkoxy-C _1-3 -alkyl, C _1-3 -alkoxycarbonyl-C _1-3 -alkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy- C _1-3 - alkyl, C _1-3 - alkylamino, N- phenylamino, N- (phenyl -
C _1-3 -alkyl) amino, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3
-Alkyl) amino, N- (C _1-3 -alkyl) -N-phenylamino, amino-C _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl, N-phenylamino- C _1-3 -alkyl, N-phenyl-C _1-3 -alkylamino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3 -alkylamino-
C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-phenylamino-C _1-3 -alkyl, phenyloxy, phenyl-C _1-3 -alkoxy, phenylthio, phenyl-C _1-3 - alkylthio, C _1-3 - alkylsulphinyl, C _1-3 - alkyl, aminosulfonyl, C _1-3 - alkyl aminosulfonyl, N- phenylamino, phenylsulfonyl and N-(C _1-3 - alkyl) −
A group selected from N- phenylaminosulfonyl; R ⁶ is methyl or amino A compound according to claim 17; a pharmaceutically acceptable salt, tautomer or prodrug. 19. The compound according to claim 18, wherein R ⁴ is optionally substituted cyclohexyl. 20. The compound according to claim 18, wherein R ⁴ is optionally substituted pyridinyl. 21. R ⁴ is phenyl optionally substituted, claim 1
8. The compound according to 8. 22. R ⁴ is cyclohexyl, pyridinyl or phenyl, wherein cyclohexyl, pyridinyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, Amino, methylamino,
19. A compound according to claim 18, optionally substituted with one, two or three groups selected from phenylamino, nitro, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio. 23. R ⁵ is hydride, fluoro, chloro, bromo, methyl,
Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl, phenyloxymethyl, methoxyphenylmethoxymethyl,
Methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino, N-phenylamino, N- ( Phenylmethyl) amino, N-methyl-
N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N-phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N- Methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, methylsulfonyl, aminosulfonyl,
19. The compound according to claim 18, which is a group selected from methylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N-methyl-N-phenylaminosulfonyl. 24. R ⁴ is cyclohexyl or phenyl, and said cyclohexyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino. , Phenylamino, nitro,
It may be substituted with one, two or three groups selected from methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio; R ⁵ is hydride, fluoro, chloro, bromo, methyl, Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl,
Phenyloxymethyl, methoxyphenylmethoxymethyl, methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino , N-phenylamino, N- (phenylmethyl) amino, N-methyl-N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N- Phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N-methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, Chirusuruhoniru, aminosulfonyl, methylaminosulfonyl, N- phenylamino, phenylsulfonyl and N- methyl -
The compound according to claim 18, which is a group selected from N-phenylaminosulfonyl. 25. Formula IIA: [Wherein R ⁴ , R ⁵ and R ⁶ are as defined in claim 24. ] The compound of Claim 24 which has these. 26. Formula IIB: [Wherein R ⁴ , R ⁵ and R ⁶ are as defined in claim 24. ] The compound of Claim 24 which has these. 27. R ⁴ is cyclohexyl or phenyl, wherein said cyclohexyl and phenyl are halo, cyano, C _1-2 -alkyl, C _1-2 -haloalkyl, C _1-2 -alkoxy and C _1-2. One selected from haloalkoxy,
It may be substituted with 2 or 3 groups; R ⁵ is hydride, C _1-2 -alkyl, C _1-3 -alkoxy, C _1-3 -alkylcarbonyl, C _1-3 -haloalkyl, C _1-3 - hydroxyalkyl and C _1-3 - is a group selected from alkoxycarbonyl, a compound according to claim 18. 28. R ⁴ is cyclohexyl or phenyl, said cyclohexyl and phenyl being one selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro, bromo and methoxy, Optionally substituted with 2 or 3 groups; R ⁵ is a group selected from hydride, methyl, methoxy, methylcarbonyl, trifluoromethyl, difluoromethyl, hydroxymethyl and methoxycarbonyl. The compound according to. 29. A compound of formula I is represented by: 19. or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 30. A compound of formula I is represented by: 19. or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 31. Formula III: [Wherein R ⁷ is cyclohexyl, pyridinyl or phenyl, and cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl, cyano, carboxyl, C _1-2 -alkoxycarbonyl, Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl,
C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ⁸ is hydrido, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 -alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 -haloalkyl, heterocyclyl, cycloalkenyl, phenyl-C _1-3 -alkyl, heterocyclyl-C _1-3 -alkyl, C _1-3 -alkylthio-C _1-3 -alkyl, C _1-3 -hydroxyalkyl,
C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3 -alkyl, phenylthio-C _1-3 -Alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _{1- 3} -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkylamino, N-arylamino, N - aralkylamino, N- (C _1-3 - alkyl) -N- aralkylamino, N- (C _{1 -3} - alkyl) - N-arylamino, amino-C _1-3 -alkyl, C _1-3 -alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-
C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-
C _1-3 -alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-
Phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl,
C _1-3 -alkylsulfonyl, aminosulfonyl, C _1-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3
- alkyl) -N- be a group selected from phenyl aminosulfonyl; R ⁹ is methyl or amino. ] The compound of Claim 1 which has these; or its pharmaceutically acceptable salt, a tautomer, or a prodrug. 32. R ⁷ is cyclohexyl, pyridinyl, or phenyl, wherein cyclohexyl, pyridinyl and phenyl, C _1-2 - alkyl, C _{1 -2} - haloalkyl, cyano, carboxyl, C _1-2 - alkoxycarbonyl , Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2-.
Alkyl, C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ⁸ is, Hydride, halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, (5- or 6-membered ring heterocyclyl). R) oxy, C _1-3 -alkoxy, C _1-3 -alkylthio, C _1-3 -alkylcarbonyl, C _3-6 -cycloalkyl, phenyl, C _1-3
-Haloalkyl, 5- or 6-membered ring heterocyclyl, C _3-6 -cycloalkenyl, phenyl-C _1-3 -alkyl, (5- or 6-membered ring heterocyclyl)
-C _1-3 -alkyl, C _1-3 -alkylthio-C _1-3 -alkyl, C _1-3 -hydroxyalkyl, C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-
C _1-3 - alkylcarbonyl, phenyl -C _2-3 - alkenyl, C _1-3 - alkoxy -C _1-3 - alkyl, phenylthio -C _1-3 - alkyl, phenyloxy -C _1-3 - alkyl, C _1-3 -alkoxyphenyl-C _1-3 -alkoxy-C _1-3 -alkyl, C _1-3 -alkoxycarbonyl-C _1-3 -alkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy- C _1-3 - alkyl, C _1-3 - alkylamino, N- phenylamino, N- (phenyl -
C _1-3 -alkyl) amino, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3
-Alkyl) amino, N- (C _1-3 -alkyl) -N-phenylamino, amino-C _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl, N-phenylamino- C _1-3 -alkyl, N-phenyl-C _1-3 -alkylamino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-phenyl-C _1-3 -alkylamino-C _1-3 - alkyl, N-(C _1-3 - alkyl) -N- phenylamino -C _1-3 - alkyl, phenyloxy, phenyl -C _1-3 - alkoxy, phenylthio, phenyl -C _1-3 - alkylthio, C _1-3 - alkylsulphinyl, C _1-3 - alkyl, aminosulfonyl, C _1-3 - alkyl aminosulfonyl, N- phenylamino, phenylsulfonyl and N-(C _1-3 - alkyl) - N
-A group selected from phenylaminosulphonyl; R ⁹ is methyl or amino; a compound according to claim 31; a pharmaceutically acceptable salt, tautomer or prodrug thereof. 33. The compound of claim 32, wherein R ⁷ may be substituted cyclohexyl. 34. The compound of claim 32, wherein R ⁷ is an optionally substituted pyridinyl. 35. R ⁷ is a phenyl optionally substituted, claim 3
The compound according to 2. 36. R ⁷ is cyclohexyl, pyridinyl or phenyl, said cyclohexyl, pyridinyl and phenyl being methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, Amino, methylamino,
33. A compound according to claim 32, optionally substituted with one, two or three groups selected from phenylamino, nitro, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio. 37. R ⁸ is hydride, fluoro, chloro, bromo, methyl,
Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl, phenyloxymethyl, methoxyphenylmethoxymethyl,
Methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino, N-phenylamino, N- ( Phenylmethyl) amino, N-methyl-
N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N-phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N- Methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, methylsulfonyl, aminosulfonyl,
33. The compound according to claim 32, which is a group selected from methylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N-methyl-N-phenylaminosulfonyl. 38. R ⁷ is cyclohexyl or phenyl, and said cyclohexyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino. , Phenylamino, nitro,
It may be substituted with one, two or three groups selected from methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio; R ⁸ is hydride, fluoro, chloro, bromo, methyl, Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl,
Phenyloxymethyl, methoxyphenylmethoxymethyl, methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino , N-phenylamino, N- (phenylmethyl) amino, N-methyl-N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N- Phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N-methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, Chirusuruhoniru, aminosulfonyl, methylaminosulfonyl, N- phenylamino, phenylsulfonyl and N- methyl -
33. The compound according to claim 32, which is a group selected from N-phenylaminosulfonyl. 39. Formula IIIA: [Wherein R ⁷ , R ⁸ and R ⁹ are as defined in claim 38]. ] The compound of Claim 38 which has these. 40. R ⁷ is cyclohexyl or phenyl, wherein said cyclohexyl and phenyl are halo, cyano, C _1-2 -alkyl, C _1-2 -haloalkyl, C _1-2 -alkoxy and C _1-2. One selected from haloalkoxy,
It may be substituted with 2 or 3 groups; R ⁸ is hydride, halogen, C _1-2 -alkyl, C _1-3 -alkoxy, C _1-3 —
33. The compound according to claim 32, which is a group selected from alkylcarbonyl, C _1-3 -haloalkyl, C _1-3 -hydroxyalkyl and C _1-3 -alkoxycarbonyl. 41. R ⁷ is cyclohexyl or phenyl, wherein said cyclohexyl and phenyl are selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro, bromo, iodo and methoxy. One, two, or three groups; R ⁸ is hydride, chloro, fluoro, bromo, cyano, methyl, methoxy,
33. A compound according to claim 32 which is a group selected from methylcarbonyl, trifluoromethyl, difluoromethyl, hydroxymethyl and methoxycarbonyl. 42. Formula IV: [Wherein R ¹⁰ is cyclohexyl, pyridinyl or phenyl, and cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl, cyano, carboxyl, C _1-2 -alkoxycarbonyl, Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl,
C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ¹¹ is hydrido, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 -alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 -haloalkyl, heterocyclyl,
Cycloalkenyl, phenyl -C _1-3 - alkyl, heterocyclyl -C _1-3 - alkyl, C _1-3 - alkylthio -C _1-3 - alkyl, C _1-3 - hydroxyalkyl, C _1-3 - Alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3-
Alkyl, phenylthio-C _1-3 -alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylamino Carbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkyl Amino, N-arylamino, N-
Aralkylamino, N- (C _1-3 -alkyl) -N-aralkylamino, N- (
C _1-3 -alkyl) -N-arylamino, amino-C _1-3 -alkyl, C _1-3-
Alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3- Alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl)-
N-phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl, C _1-3 -alkylsulfonyl, aminosulfonyl, C ₁ A group selected from _-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3 -alkyl) -N-phenylaminosulfonyl; R ¹² is methyl or amino, However, when R ¹⁰ is 4-bromophenyl, R ¹¹ is not methyl. ] The compound of Claim 1 which has these; or its pharmaceutically acceptable salt, a tautomer, or a prodrug. 43. R ¹⁰ is cyclohexyl, pyridinyl, or phenyl, wherein cyclohexyl, pyridinyl and phenyl, C _1-2 - alkyl, C _{1 -2} - haloalkyl, cyano, carboxyl, C _1-2 - alkoxycarbonyl , Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2-.
Alkyl, C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ¹¹ is, Hydride, halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, (5-
Or 6-membered ring heterocyclyl) oxy, C _1-3 - alkoxy, C _1-3 - alkylthio, C _1-3 - alkylcarbonyl, C _3-6 - cycloalkyl, phenyl, C _1-3 - haloalkyl, 5- or 6-membered ring heterocyclyl, C _3-6 -cycloalkenyl, phenyl-C _1-3 -alkyl, (5- or 6-membered ring heterocyclyl)
-C _1-3 -alkyl, C _1-3 -alkylthio-C _1-3 -alkyl, C _1-3 -hydroxyalkyl, C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-
C _1-3 - alkylcarbonyl, phenyl -C _2-3 - alkenyl, C _1-3 - alkoxy -C _1-3 - alkyl, phenylthio -C _1-3 - alkyl, phenyloxy -C _1-3 - alkyl, C _1-3 -alkoxyphenyl-C _1-3 -alkoxy-C _1-3 -alkyl, C _1-3 -alkoxycarbonyl-C _1-3 -alkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy- C _1-3 - alkyl, C _1-3 - alkylamino, N- phenylamino, N- (phenyl -
C _1-3 -alkyl) amino, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3
-Alkyl) amino, N- (C _1-3 -alkyl) -N-phenylamino, amino-C _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl, N-phenylamino- C _1-3 -alkyl, N-phenyl-C _1-3 -alkylamino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-phenyl-C _1-3 -alkylamino-C _1-3 - alkyl, N-(C _1-3 - alkyl) -N- phenylamino -C _1-3 - alkyl, phenyloxy, phenyl -C _1-3 - alkoxy, phenylthio, phenyl -C _1-3 - alkylthio, C _1-3 - alkylsulphinyl, C _1-3 - alkyl, aminosulfonyl, C _1-3 - alkyl aminosulfonyl, N- phenylamino, phenylsulfonyl and N-(C _1-3 - alkyl) - N
- a group selected from phenyl aminosulfonyl; R ¹² is methyl or amino A compound according to claim 42; a pharmaceutically acceptable salt, tautomer or prodrug. 44. The compound according to claim 43, wherein R ¹⁰ is optionally substituted cyclohexyl. 45. The compound of claim 43, wherein R ¹⁰ is optionally substituted pyridinyl. 46. R ¹⁰ is phenyl which may be substituted, claim 4
The compound according to 3. 47. R ¹⁰ is cyclohexyl, pyridinyl or phenyl, wherein cyclohexyl, pyridinyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, Amino, methylamino,
44. The compound according to claim 43, optionally substituted with one, two or three groups selected from phenylamino, nitro, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio. 48. R ¹¹ is hydride, fluoro, chloro, bromo, methyl,
Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl, phenyloxymethyl, methoxyphenylmethoxymethyl,
Methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino, N-phenylamino, N- ( Phenylmethyl) amino, N-methyl-
N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N-phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N- Methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, methylsulfonyl, aminosulfonyl,
44. A compound according to claim 43 which is a group selected from methylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N-methyl-N-phenylaminosulfonyl. 49. R ¹⁰ is cyclohexyl or phenyl, and said cyclohexyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino. , Phenylamino, nitro,
It may be substituted with one, two or three groups selected from methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio; R ¹¹ is hydride, fluoro, chloro, bromo, methyl, Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl,
Phenyloxymethyl, methoxyphenylmethoxymethyl, methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino , N-phenylamino, N- (phenylmethyl) amino, N-methyl-N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N- Phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N-methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, Chirusuruhoniru, aminosulfonyl, methylaminosulfonyl, N- phenylamino, phenylsulfonyl and N- methyl -
44. The compound according to claim 43, which is a group selected from N-phenylaminosulfonyl. 50. Formula IVA: embedded image [Wherein R ¹⁰ , R ¹¹ and R ¹² are as defined in claim 49. ] The compound of Claim 49 which has these. 51. Formula IVB: [Wherein R ¹⁰ , R ¹¹ and R ¹² are as defined in claim 49. ] The compound of Claim 49 which has these. 52. R ¹⁰ is cyclohexyl or phenyl, wherein said cyclohexyl and phenyl are halo, cyano, C _1-2 -alkyl, C _1-2 -haloalkyl, C _1-2 -alkoxy and C _1-2. One selected from haloalkoxy,
It may be substituted with 2 or 3 groups; R ¹¹ is hydride, C _1-2 -alkyl, C _1-3 -alkoxy, C _1-3 -alkylcarbonyl, C _1-3 -haloalkyl, C 1. _1-3 -hydroxyalkyl and C _1-3 −
44. The compound according to claim 43, which is a group selected from alkoxycarbonyl. 53. R ¹⁰ is cyclohexyl or phenyl, said cyclohexyl and phenyl being one selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro, bromo and methoxy, 44. It may be substituted with 2 or 3 groups; R ¹¹ is a group selected from hydride, methyl, methoxy, methylcarbonyl, trifluoromethyl, difluoromethyl, hydroxymethyl and methoxycarbonyl. The compound according to. 54. A compound of formula I is represented by: 50; or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 55. Formula V: embedded image [Wherein, R ¹³ is cyclohexyl, pyridinyl or phenyl, and cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl, cyano, carboxyl, C _1-2 -alkoxycarbonyl, Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl,
C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ¹⁴ is hydrido, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 -alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 -haloalkyl, heterocyclyl,
Cycloalkenyl, phenyl -C _1-3 - alkyl, heterocyclyl -C _1-3 - alkyl, C _1-3 - alkylthio -C _1-3 - alkyl, C _1-3 - hydroxyalkyl, C _1-3 - Alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3-
Alkyl, phenylthio-C _1-3 -alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylamino Carbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkyl Amino, N-arylamino, N-
Aralkylamino, N- (C _1-3 -alkyl) -N-aralkylamino, N- (
C _1-3 -alkyl) -N-arylamino, amino-C _1-3 -alkyl, C _1-3-
Alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3- Alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl)-
N-phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl, C _1-3 -alkylsulfonyl, aminosulfonyl, C ₁ A group selected from _-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3 -alkyl) -N-phenylaminosulfonyl; R ¹⁵ is methyl or amino, However, when R ¹³ is 4-bromophenyl, R ¹⁴ is not hydrogen. ] The compound of Claim 1 which has these; or its pharmaceutically acceptable salt, a tautomer, or a prodrug. 56. R ¹³ is cyclohexyl, pyridinyl, or phenyl, wherein cyclohexyl, pyridinyl and phenyl, C _1-2 - alkyl, C _{1 -2} - haloalkyl, cyano, carboxyl, C _1-2 - alkoxycarbonyl , Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2-.
Alkyl, C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ¹⁴ is, Hydride, halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, (5-
Or 6-membered ring heterocyclyl) oxy, C _1-3 - alkoxy, C _1-3 - alkylthio, C _1-3 - alkylcarbonyl, C _3-6 - cycloalkyl, phenyl, C _1-3 - haloalkyl, 5- or 6-membered ring heterocyclyl, C _3-6 -cycloalkenyl, phenyl-C _1-3 -alkyl, (5- or 6-membered ring heterocyclyl)
-C _1-3 -alkyl, C _1-3 -alkylthio-C _1-3 -alkyl, C _1-3 -hydroxyalkyl, C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-
C _1-3 - alkylcarbonyl, phenyl -C _2-3 - alkenyl, C _1-3 - alkoxy -C _1-3 - alkyl, phenylthio -C _1-3 - alkyl, phenyloxy -C _1-3 - alkyl, C _1-3 -alkoxyphenyl-C _1-3 -alkoxy-C _1-3 -alkyl, C _1-3 -alkoxycarbonyl-C _1-3 -alkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy- C _1-3 - alkyl, C _1-3 - alkylamino, N- phenylamino, N- (phenyl -
C _1-3 -alkyl) amino, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3
-Alkyl) amino, N- (C _1-3 -alkyl) -N-phenylamino, amino-C _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl, N-phenylamino- C _1-3 -alkyl, N-phenyl-C _1-3 -alkylamino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-phenyl-C _1-3 -alkylamino-C _1-3 - alkyl, N-(C _1-3 - alkyl) -N- phenylamino -C _1-3 - alkyl, phenyloxy, phenyl -C _1-3 - alkoxy, phenylthio, phenyl -C _1-3 - alkylthio, C _1-3 - alkylsulphinyl, C _1-3 - alkyl, aminosulfonyl, C _1-3 - alkyl aminosulfonyl, N- phenylamino, phenylsulfonyl and N-(C _1-3 - alkyl) - N
A compound according to claim 55, wherein R ¹⁵ is methyl or amino; or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 57. The compound according to claim 56, wherein R ¹³ is optionally substituted cyclohexyl. 58. The compound of claim 56, wherein R ¹³ is an optionally substituted pyridinyl. 59. The method of claim 5, wherein R ¹³ is optionally substituted phenyl.
The compound according to 6. 60. R ¹³ is cyclohexyl, pyridinyl or phenyl, wherein said cyclohexyl, pyridinyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, Amino, methylamino,
57. The compound of claim 56, optionally substituted with one, two or three groups selected from phenylamino, nitro, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio. 61. R ¹⁴ is hydride, fluoro, chloro, bromo, methyl,
Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl, phenyloxymethyl, methoxyphenylmethoxymethyl,
Methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino, N-phenylamino, N- ( Phenylmethyl) amino, N-methyl-
N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N-phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N- Methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, methylsulfonyl, aminosulfonyl,
57. The compound of claim 56, which is a group selected from methylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N-methyl-N-phenylaminosulfonyl. 62. R ¹³ is cyclohexyl or phenyl, and said cyclohexyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino. , Phenylamino, nitro,
It may be substituted with one, two or three groups selected from methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio; R ¹⁴ is hydride, fluoro, chloro, bromo, methyl, Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl,
Phenyloxymethyl, methoxyphenylmethoxymethyl, methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino , N-phenylamino, N- (phenylmethyl) amino, N-methyl-N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N- Phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N-methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, Chirusuruhoniru, aminosulfonyl, methylaminosulfonyl, N- phenylamino, phenylsulfonyl and N- methyl -
57. The compound of claim 56, which is a group selected from N-phenylaminosulfonyl. 63. Formula VA: embedded image [Wherein R ¹³ , R ¹⁴ and R ¹⁵ are defined in claim 62. ] The compound of Claim 62 which has these. 64. Formula VB: [Wherein R ¹³ , R ¹⁴ and R ¹⁵ are defined in claim 62. ] The compound of Claim 62 which has these. 65. R ¹³ is cyclohexyl or phenyl, wherein said cyclohexyl and phenyl are halo, cyano, C _1-2 -alkyl, C _1-2 -haloalkyl, C _1-2 -alkoxy and C _1-2. One selected from haloalkoxy,
It may be substituted with 2 or 3 groups; R ¹⁴ is hydride, C _1-2 -alkyl, C _1-3 -alkoxy, C _1-3 -alkylcarbonyl, C _1-3 -haloalkyl, C _1-3 -hydroxyalkyl and C _1-3 −
57. The compound of claim 56, which is a group selected from alkoxycarbonyl. 66. R ¹³ is cyclohexyl or phenyl, said cyclohexyl and phenyl being one selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro, bromo and methoxy, 57. Optionally substituted with 2 or 3 groups; R ¹⁴ is a group selected from hydride, methyl, methoxy, methylcarbonyl, trifluoromethyl, difluoromethyl, hydroxymethyl and methoxycarbonyl. The compound according to. 67. A compound of formula I is: 63; or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 68. Formula VI: [In the formula, R ¹⁶ is cyclohexyl, pyridinyl or phenyl, and the cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl, cyano, carboxyl, C _1-2 -alkoxycarbonyl, Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl,
C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ¹⁷ is hydrido, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 -alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 -haloalkyl, heterocyclyl,
Cycloalkenyl, phenyl -C _1-3 - alkyl, heterocyclyl -C _1-3 - alkyl, C _1-3 - alkylthio -C _1-3 - alkyl, C _1-3 - hydroxyalkyl, C _1-3 - Alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3-
Alkyl, phenylthio-C _1-3 -alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylamino Carbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkyl Amino, N-arylamino, N-
Aralkylamino, N- (C _1-3 -alkyl) -N-aralkylamino, N- (
C _1-3 -alkyl) -N-arylamino, amino-C _1-3 -alkyl, C _1-3-
Alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3- Alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl)-
N-phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl, C _1-3 -alkylsulfonyl, aminosulfonyl, C ₁ Is a group selected from _-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3 -alkyl) -N-phenylaminosulfonyl; R ¹⁸ is methyl or amino. ] The compound of Claim 1 which has these; or its pharmaceutically acceptable salt, a tautomer, or a prodrug. 69. R ¹⁶ is cyclohexyl, pyridinyl, or phenyl, wherein cyclohexyl, pyridinyl and phenyl, C _1-2 - alkyl, C _{1 -2} - haloalkyl, cyano, carboxyl, C _1-2 - alkoxycarbonyl , Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2-.
Alkyl, C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ¹⁷ is, Hydride, halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, (5-
Or 6-membered ring heterocyclyl) oxy, C _1-3 - alkoxy, C _1-3 - alkylthio, C _1-3 - alkylcarbonyl, C _3-6 - cycloalkyl, phenyl, C _1-3 - haloalkyl, 5- or 6-membered ring heterocyclyl, C _3-6 -cycloalkenyl, phenyl-C _1-3 -alkyl, (5- or 6-membered ring heterocyclyl)
-C _1-3 -alkyl, C _1-3 -alkylthio-C _1-3 -alkyl, C _1-3 -hydroxyalkyl, C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-
C _1-3 - alkylcarbonyl, phenyl -C _2-3 - alkenyl, C _1-3 - alkoxy -C _1-3 - alkyl, phenylthio -C _1-3 - alkyl, phenyloxy -C _1-3 - alkyl, C _1-3 -alkoxyphenyl-C _1-3 -alkoxy-C _1-3 -alkyl, C _1-3 -alkoxycarbonyl-C _1-3 -alkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy- C _1-3 - alkyl, C _1-3 - alkylamino, N- phenylamino, N- (phenyl -
C _1-3 -alkyl) amino, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3
-Alkyl) amino, N- (C _1-3 -alkyl) -N-phenylamino, amino-C _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl, N-phenylamino- C _1-3 -alkyl, N-phenyl-C _1-3 -alkylamino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-phenyl-C _1-3 -alkylamino-C _1-3 - alkyl, N-(C _1-3 - alkyl) -N- phenylamino -C _1-3 - alkyl, phenyloxy, phenyl -C _1-3 - alkoxy, phenylthio, phenyl -C _1-3 - alkylthio, C _1-3 - alkylsulphinyl, C _1-3 - alkyl, aminosulfonyl, C _1-3 - alkyl aminosulfonyl, N- phenylamino, phenylsulfonyl and N-(C _1-3 - alkyl) - N
69. A compound according to claim 68 wherein R ¹⁸ is methyl or amino; or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 70. The compound according to claim 69, wherein R ¹⁶ is optionally substituted cyclohexyl. 71. The compound of claim 69, wherein R ¹⁶ is optionally substituted pyridinyl. 72. The method of claim 6 wherein R ¹⁶ is an optionally substituted phenyl.
9. The compound according to 9. 73. R ¹⁶ is cyclohexyl, pyridinyl or phenyl, wherein said cyclohexyl, pyridinyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, Amino, methylamino,
70. The compound of claim 69, optionally substituted with one, two or three groups selected from phenylamino, nitro, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio. 74. R ¹⁷ is hydride, fluoro, chloro, bromo, methyl,
Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl, phenyloxymethyl, methoxyphenylmethoxymethyl,
Methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino, N-phenylamino, N- ( Phenylmethyl) amino, N-methyl-
N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N-phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N- Methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, methylsulfonyl, aminosulfonyl,
70. The compound of claim 69, which is a group selected from methylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N-methyl-N-phenylaminosulfonyl. 75. R ¹⁶ is cyclohexyl or phenyl, and said cyclohexyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino. , Phenylamino, nitro,
It may be substituted with one, two or three groups selected from methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio; R ¹⁷ is hydride, fluoro, chloro, bromo, methyl, Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl,
Phenyloxymethyl, methoxyphenylmethoxymethyl, methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino , N-phenylamino, N- (phenylmethyl) amino, N-methyl-N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N- Phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N-methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, Chirusuruhoniru, aminosulfonyl, methylaminosulfonyl, N- phenylamino, phenylsulfonyl and N- methyl -
70. The compound of claim 69, which is a group selected from N-phenylaminosulfonyl. 76. Formula VIA: [Wherein R ¹⁶ , R ¹⁷ and R ¹⁸ are defined in claim 75. ] The compound of Claim 75 which has these. 77. R ¹⁶ is cyclohexyl or phenyl, wherein said cyclohexyl and phenyl are halo, cyano, C _1-2 -alkyl, C _1-2 -haloalkyl, C _1-2 -alkoxy and C _1-2. One selected from haloalkoxy,
It may be substituted with 2 or 3 groups; R ¹⁷ is hydride, C _1-2 -alkyl, C _1-3 -alkoxy, C _1-3 -alkylcarbonyl, C _1-3 -haloalkyl, C _1-3 -hydroxyalkyl and C _1-3 −
70. The compound of claim 69, which is a group selected from alkoxycarbonyl. 78. R ¹⁶ is cyclohexyl or phenyl, said cyclohexyl and phenyl being one selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro, bromo and methoxy, 71. It may be substituted with 2 or 3 groups; R ¹⁷ is a group selected from hydride, methyl, methoxy, methylcarbonyl, trifluoromethyl, difluoromethyl, hydroxymethyl and methoxycarbonyl. The compound according to. 79. A compound of formula I is represented by: Or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 80. Formula VII: embedded image [In the formula, R ¹⁹ is cyclohexyl, pyridinyl or phenyl, and the cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl, cyano, carboxyl, C _1-2 -alkoxycarbonyl, Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl,
C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ²⁰ is hydrido, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 -alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 -haloalkyl, heterocyclyl,
Cycloalkenyl, phenyl -C _1-3 - alkyl, heterocyclyl -C _1-3 - alkyl, C _1-3 - alkylthio -C _1-3 - alkyl, C _1-3 - hydroxyalkyl, C _1-3 - Alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3-
Alkyl, phenylthio-C _1-3 -alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylamino Carbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkyl Amino, N-arylamino, N-
Aralkylamino, N- (C _1-3 -alkyl) -N-aralkylamino, N- (
C _1-3 -alkyl) -N-arylamino, amino-C _1-3 -alkyl, C _1-3-
Alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3- Alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl)-
N-phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl, C _1-3 -alkylsulfonyl, aminosulfonyl, C ₁ Is one or more groups selected from _-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3 -alkyl) -N-phenylaminosulfonyl; R ²¹ is methyl or It is Amino. ] The compound of Claim 1 which has these; or its pharmaceutically acceptable salt, a tautomer, or a prodrug. 81. R ¹⁹ is cyclohexyl, pyridinyl, or phenyl, wherein cyclohexyl, pyridinyl and phenyl, C _1-2 - alkyl, C _{1 -2} - haloalkyl, cyano, carboxyl, C _1-2 - alkoxycarbonyl , Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2-.
Alkyl, C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ²⁰ is, Hydride, halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, (5-
Or 6-membered ring heterocyclyl) oxy, C _1-3 - alkoxy, C _1-3 - alkylthio, C _1-3 - alkylcarbonyl, C _3-6 - cycloalkyl, phenyl, C _1-3 - haloalkyl, 5- or 6-membered ring heterocyclyl, C _3-6 -cycloalkenyl, phenyl-C _1-3 -alkyl, (5- or 6-membered ring heterocyclyl)
-C _1-3 -alkyl, C _1-3 -alkylthio-C _1-3 -alkyl, C _1-3 -hydroxyalkyl, C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-
C _1-3 - alkylcarbonyl, phenyl -C _2-3 - alkenyl, C _1-3 - alkoxy -C _1-3 - alkyl, phenylthio -C _1-3 - alkyl, phenyloxy -C _1-3 - alkyl, C _1-3 -alkoxyphenyl-C _1-3 -alkoxy-C _1-3 -alkyl, C _1-3 -alkoxycarbonyl-C _1-3 -alkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy- C _1-3 - alkyl, C _1-3 - alkylamino, N- phenylamino, N- (phenyl -
C _1-3 -alkyl) amino, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3
-Alkyl) amino, N- (C _1-3 -alkyl) -N-phenylamino, amino-C _1-3 -alkyl, C _1-3 -alkylamino-C _1-3 -alkyl, N-phenylamino- C _1-3 -alkyl, N-phenyl-C _1-3 -alkylamino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-phenyl-C _1-3 -alkylamino-C _1-3 - alkyl, N-(C _1-3 - alkyl) -N- phenylamino -C _1-3 - alkyl, phenyloxy, phenyl -C _1-3 - alkoxy, phenylthio, phenyl -C _1-3 - alkylthio, C _1-3 - alkylsulphinyl, C _1-3 - alkyl, aminosulfonyl, C _1-3 - alkyl aminosulfonyl, N- phenylamino, phenylsulfonyl and N-(C _1-3 - alkyl) - N
-A group selected from phenylaminosulfonyl; R ²¹ is methyl or amino; a compound of claim 80; or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 82. The compound of claim 81, wherein R ¹⁹ is optionally substituted cyclohexyl. 83. The compound of claim 81, wherein R ¹⁹ is optionally substituted pyridinyl. 84. The method of claim 8 wherein R ¹⁹ is an optionally substituted phenyl.
The compound according to 1. 85. R ¹⁹ is cyclohexyl, pyridinyl or phenyl, and said cyclohexyl, pyridinyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, Amino, methylamino,
82. The compound of claim 81, optionally substituted with one, two or three groups selected from phenylamino, nitro, methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio. 86. R ²⁰ is hydride, fluoro, chloro, bromo, methyl,
Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl, phenyloxymethyl, methoxyphenylmethoxymethyl,
Methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino, N-phenylamino, N- ( Phenylmethyl) amino, N-methyl-
N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N-phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N- Methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, methylsulfonyl, aminosulfonyl,
82. A compound according to claim 81 which is a group selected from methylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N-methyl-N-phenylaminosulfonyl. 87. R ¹⁹ is cyclohexyl or phenyl, and said cyclohexyl and phenyl are methyl, difluoromethyl, trifluoromethyl, cyano, carboxyl, methoxycarbonyl, hydroxyl, hydroxymethyl, trifluoromethoxy, amino, methylamino. , Phenylamino, nitro,
It may be substituted with one, two or three groups selected from methoxymethyl, methylsulfinyl, fluoro, chloro, bromo, methoxy and methylthio; R ²⁰ is hydride, fluoro, chloro, bromo, methyl, Oxo, cyano, carboxyl, cyanomethyl, methoxy, methylthio, methylcarbonyl, phenyl, trifluoromethyl, difluoromethyl, phenylmethyl, methylthiomethyl, hydroxymethyl, methoxycarbonyl, ethoxycarbonyl, phenylcarbonyl, phenylmethylcarbonyl, methoxymethyl, phenyl Thiomethyl,
Phenyloxymethyl, methoxyphenylmethoxymethyl, methoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, methylaminocarbonyl, N-phenylaminocarbonyl, N-methyl-N-phenylaminocarbonyl, methylaminocarbonylmethyl, carboxymethyl, methylamino , N-phenylamino, N- (phenylmethyl) amino, N-methyl-N- (phenylmethyl) amino, N-methyl-N-phenylamino, aminomethyl, methylaminomethyl, N-phenylaminomethyl, N- Phenylmethylaminomethyl, N-methyl-N-phenylmethylaminomethyl, N-methyl-N-phenylaminomethyl, phenyloxy, phenylmethoxy, phenylthio, phenylmethylthio, methylsulfinyl, Chirusuruhoniru, aminosulfonyl, methylaminosulfonyl, N- phenylamino, phenylsulfonyl and N- methyl -
82. The compound of claim 81, which is a group selected from N-phenylaminosulfonyl. 88. Formula VIIA: embedded image [Wherein R ¹⁹ , R ²⁰ and R ²¹ are as defined in claim 87. ] The compound of Claim 87 which has these. 89. R ¹⁹ is cyclohexyl or phenyl, wherein said cyclohexyl and phenyl are halo, cyano, C _1-2 -alkyl, C _1-2 -haloalkyl, C _1-2 -alkoxy and C _1-2. One selected from haloalkoxy,
It may be substituted with 2 or 3 groups; R ²⁰ is hydride, C _1-2 -alkyl, C _1-3 -alkoxy, C _1-3 -alkylcarbonyl, C _1-3 -haloalkyl, C _1-3 -hydroxyalkyl and C _1-3 −
82. The compound of claim 81, which is a group selected from alkoxycarbonyl. 90. R ¹⁹ is cyclohexyl or phenyl, wherein said cyclohexyl and phenyl are one selected from methyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, cyano, fluoro, chloro, bromo and methoxy, 82. It may be substituted with 2 or 3 groups; R ²⁰ is a group selected from hydride, methyl, methoxy, methylcarbonyl, trifluoromethyl, difluoromethyl, hydroxymethyl and methoxycarbonyl. The compound according to. 91. A compound of formula I is represented by: 89. or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 92. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1. 93. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 17. 94. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 31. 95. A pharmaceutical composition comprising a therapeutically effective amount of the compound represented by claim 42. 96. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 55. 97. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 68. 98. A pharmaceutical composition comprising a therapeutically effective amount of the compound represented by claim 80. 99. A method of treating inflammation, which method comprises administering to a patient having or susceptible to such inflammation or inflammation-related disease, Formula I: [Wherein ^A is a 5- or 6-membered ring substituent selected from partially saturated or unsaturated heterocyclic and carbocyclic rings; R ¹ is cyclohexyl, pyridinyl or phenyl; Wherein cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl,
Cyano, carboxyl, C _1-2 -alkoxycarbonyl, hydroxyl, C _1-2-
Hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl, C _1-2 -alkylsulfinyl, halo, It may be substituted with 1, 2 or 3 groups selected from C _1-2 -alkoxy and C _1-3 -alkylthio; R ² is methyl or amino; R ³ is hydride, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 - alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 - haloalkyl, heterocyclyl, cycloalkenyl, phenyl -C _1-3 - alkyl, heterocyclyl -C _1-3 - Alkyl, C _1-3 - alkylthio -C _1-3 - alkyl, C _1-3 - hydroxyalkyl,
C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3 -alkyl, phenylthio-C _1-3 -Alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _{1- 3} -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkylamino, N-arylamino, N - aralkylamino, N- (C _1-3 - alkyl) -N- aralkylamino, N- (C _{1 -3} - alkyl) - N-arylamino, amino-C _1-3 -alkyl, C _1-3 -alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-
C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-
C _1-3 -alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-
Phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl,
C _1-3 -alkylsulfonyl, aminosulfonyl, C _1-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3
Represents one or more groups selected from -alkyl) -N-phenylaminosulfonyl. ] Or a pharmaceutically acceptable salt, tautomer or prodrug thereof, the method comprising administering a therapeutically effective amount thereof. 100. The compound has the formula II: [In the formula, R ⁴ is cyclohexyl, pyridinyl or phenyl, and the cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl, cyano, carboxyl, C _1-2 -alkoxycarbonyl, Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl,
C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, two or may be substituted by three radicals; is R ^5, hydrido, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 -alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 -haloalkyl, heterocyclyl, cycloalkenyl, phenyl-C _1-3 -alkyl, heterocyclyl-C _1-3 -alkyl, C _1-3 -alkylthio-C _1-3 -alkyl, C _1-3 -hydroxyalkyl,
C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3 -alkyl, phenylthio-C _1-3 -Alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _{1- 3} -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkylamino, N-arylamino, N - aralkylamino, N- (C _1-3 - alkyl) -N- aralkylamino, N- (C _{1 -3} - alkyl) - N-arylamino, amino-C _1-3 -alkyl, C _1-3 -alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-
C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-
C _1-3 -alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-
Phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl,
C _1-3 -alkylsulfonyl, aminosulfonyl, C _1-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3
Represents one or more groups selected from -alkyl) -N-phenylaminosulfonyl; R < ⁶ > is methyl or amino, provided that R < ¹ > is 4-bromophenyl and R < ² > is methyl. Sometimes R ³ is not hydrogen, cyano, trifluoromethyl or ethoxycarbonyl. ]; Or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 101. The compound has the formula III: [Wherein R ⁷ is cyclohexyl, pyridinyl or phenyl, and cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl, cyano, carboxyl, C _1-2 -alkoxycarbonyl, Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl,
C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ⁸ is hydrido, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 -alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 -haloalkyl, heterocyclyl, cycloalkenyl, phenyl-C _1-3 -alkyl, heterocyclyl-C _1-3 -alkyl, C _1-3 -alkylthio-C _1-3 -alkyl, C _1-3 -hydroxyalkyl,
C _1-3 -alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3 -alkyl, phenylthio-C _1-3 -Alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylaminocarbonyl, N- (C _{1- 3} -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkylamino, N-arylamino, N - aralkylamino, N- (C _1-3 - alkyl) -N- aralkylamino, N- (C _{1 -3} - alkyl) - N-arylamino, amino-C _1-3 -alkyl, C _1-3 -alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-
C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-
C _1-3 -alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl) -N-
Phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl,
C _1-3 -alkylsulfonyl, aminosulfonyl, C _1-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3
- alkyl) -N- be a group selected from phenyl aminosulfonyl; R ⁹ is methyl or amino. ]; Or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 102. The compound has the formula IV: [Wherein R ¹⁰ is cyclohexyl, pyridinyl or phenyl, and cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl, cyano, carboxyl, C _1-2 -alkoxycarbonyl, Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl,
C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ¹¹ is hydrido, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 -alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 -haloalkyl, heterocyclyl,
Cycloalkenyl, phenyl -C _1-3 - alkyl, heterocyclyl -C _1-3 - alkyl, C _1-3 - alkylthio -C _1-3 - alkyl, C _1-3 - hydroxyalkyl, C _1-3 - Alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3-
Alkyl, phenylthio-C _1-3 -alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylamino Carbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkyl Amino, N-arylamino, N-
Aralkylamino, N- (C _1-3 -alkyl) -N-aralkylamino, N- (
C _1-3 -alkyl) -N-arylamino, amino-C _1-3 -alkyl, C _1-3-
Alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3- Alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl)-
N-phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl, C _1-3 -alkylsulfonyl, aminosulfonyl, C ₁ A group selected from _-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3 -alkyl) -N-phenylaminosulfonyl; R ¹² is methyl or amino. ]; Or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 103. The compound has the formula V: [Wherein, R ¹³ is cyclohexyl, pyridinyl or phenyl, and cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl, cyano, carboxyl, C _1-2 -alkoxycarbonyl, Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl,
C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ¹⁴ is hydrido, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 -alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 -haloalkyl, heterocyclyl,
Cycloalkenyl, phenyl -C _1-3 - alkyl, heterocyclyl -C _1-3 - alkyl, C _1-3 - alkylthio -C _1-3 - alkyl, C _1-3 - hydroxyalkyl, C _1-3 - Alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3-
Alkyl, phenylthio-C _1-3 -alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylamino Carbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkyl Amino, N-arylamino, N-
Aralkylamino, N- (C _1-3 -alkyl) -N-aralkylamino, N- (
C _1-3 -alkyl) -N-arylamino, amino-C _1-3 -alkyl, C _1-3-
Alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3- Alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl)-
N-phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl, C _1-3 -alkylsulfonyl, aminosulfonyl, C ₁ Is a group selected from _-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3 -alkyl) -N-phenylaminosulfonyl; R ¹⁵ is methyl or amino. ]; Or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 104. The compound has the formula VI: [In the formula, R ¹⁶ is cyclohexyl, pyridinyl or phenyl, and the cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl, cyano, carboxyl, C _1-2 -alkoxycarbonyl, Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl,
C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ¹⁷ is hydrido, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 -alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 -haloalkyl, heterocyclyl,
Cycloalkenyl, phenyl -C _1-3 - alkyl, heterocyclyl -C _1-3 - alkyl, C _1-3 - alkylthio -C _1-3 - alkyl, C _1-3 - hydroxyalkyl, C _1-3 - Alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3-
Alkyl, phenylthio-C _1-3 -alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylamino Carbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkyl Amino, N-arylamino, N-
Aralkylamino, N- (C _1-3 -alkyl) -N-aralkylamino, N- (
C _1-3 -alkyl) -N-arylamino, amino-C _1-3 -alkyl, C _1-3-
Alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3- Alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl)-
N-phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl, C _1-3 -alkylsulfonyl, aminosulfonyl, C ₁ Is a group selected from _-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3 -alkyl) -N-phenylaminosulfonyl; R ¹⁸ is methyl or amino. ]; Or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 105. The compound has the formula VII: [In the formula, R ¹⁹ is cyclohexyl, pyridinyl or phenyl, and the cyclohexyl, pyridinyl and phenyl are C _1-2 -alkyl, C _1-2 -haloalkyl, cyano, carboxyl, C _1-2 -alkoxycarbonyl, Hydroxyl, C _1-2 -hydroxyalkyl, C _1-2 -haloalkoxy, amino, C _1-2 -alkylamino, phenylamino, nitro, C _1-2 -alkoxy-C _1-2 -alkyl,
C _1-2 - alkylsulphinyl, halo, C _1-2 - alkoxy and C _1-3 - one selected from alkylthio, may be substituted by two or three groups; R ²⁰ is hydrido, Halo, C _1-2 -alkyl, C _2-3 -alkenyl, C _2-3 -alkynyl, oxo, cyano, carboxyl, cyano-C _1-3 -alkyl, heterocyclyloxy, C _1-3 -alkoxy, C _1-3 -alkylthio, alkylcarbonyl, cycloalkyl, phenyl, C _1-3 -haloalkyl, heterocyclyl,
Cycloalkenyl, phenyl -C _1-3 - alkyl, heterocyclyl -C _1-3 - alkyl, C _1-3 - alkylthio -C _1-3 - alkyl, C _1-3 - hydroxyalkyl, C _1-3 - Alkoxycarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, phenyl-C _2-3 -alkenyl, C _1-3 -alkoxy-C _1-3-
Alkyl, phenylthio-C _1-3 -alkyl, phenyloxyalkyl, alkoxyphenylalkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonyl-C _1-3 -alkyl, C _1-3 -alkylaminocarbonyl, N-phenylamino Carbonyl, N- (C _1-3 -alkyl) -N-phenylaminocarbonyl, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyl, carboxy-C _1-3 -alkyl, C _1-3 -alkyl Amino, N-arylamino, N-
Aralkylamino, N- (C _1-3 -alkyl) -N-aralkylamino, N- (
C _1-3 -alkyl) -N-arylamino, amino-C _1-3 -alkyl, C _1-3-
Alkylaminoalkyl, N-phenylamino-C _1-3 -alkyl, N-phenyl-C _1-3 -alkylaminoalkyl, N- (C _1-3 -alkyl) -N- (phenyl-C _1-3- Alkyl) amino-C _1-3 -alkyl, N- (C _1-3 -alkyl)-
N-phenylamino-C _1-3 -alkyl, phenyloxy, phenylalkoxy, phenylthio, phenyl-C _1-3 -alkylthio, C _1-3 -alkylsulfinyl, C _1-3 -alkylsulfonyl, aminosulfonyl, C ₁ Is one or more groups selected from _-3 -alkylaminosulfonyl, N-phenylaminosulfonyl, phenylsulfonyl and N- (C _1-3 -alkyl) -N-phenylaminosulfonyl; R ²¹ is methyl or It is Amino. ]; Or a pharmaceutically acceptable salt, tautomer or prodrug thereof. 106. The method of claim 99 used for the treatment of inflammation. 107. The method of claim 99, used in the treatment of diseases associated with inflammation. 108. The method of claim 107, wherein the disease associated with inflammation is arthritis. 109. The method of claim 107, wherein the disease associated with inflammation is pain. 110. The method of claim 107, wherein the disease associated with inflammation is fever. 111. A method of treating cancer, said method comprising administering to a patient having or suffering from such cancer a therapeutically effective amount of a compound of claim 99. How to include. 112. The method of claim 111, wherein the compound is administered intravenously. 113. The method of claim 111, wherein the compound is administered intramuscularly.